1932

Abstract

Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biophys-051013-022942
2017-05-22
2024-10-12
Loading full text...

Full text loading...

/deliver/fulltext/biophys/46/1/annurev-biophys-051013-022942.html?itemId=/content/journals/10.1146/annurev-biophys-051013-022942&mimeType=html&fmt=ahah

Literature Cited

  1. Alexander-Brett JM, Fremont DH. 1.  2007. Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor. J. Exp. Med. 204:3157–72 [Google Scholar]
  2. Andrews G, Jones C, Wreggett KA. 2.  2008. An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein–coupled receptors CCR4 and CCR5. Mol. Pharmacol. 73:855–67 [Google Scholar]
  3. Baggiolini M. 3.  1998. Chemokines and leukocyte traffic. Nature 392:565–68 [Google Scholar]
  4. Ballesteros JA, Weinstein H. 4.  1995. Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein–coupled receptors. Methods in Neurosciences: Receptor Molecular Biology SC Sealfon 366–428 San Diego: Academic [Google Scholar]
  5. Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M. 5.  et al. 2004. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. PNAS 101:11791–96 [Google Scholar]
  6. Bertini R, Barcelos LS, Beccari AR, Cavalieri B, Moriconi A. 6.  et al. 2012. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br. J. Pharmacol. 165:436–54 [Google Scholar]
  7. Blanchetot C, Verzijl D, Mujić-Delić A, Bosch L, Rem L. 7.  et al. 2013. Neutralizing nanobodies targeting diverse chemokines effectively inhibit chemokine function. J. Biol. Chem. 288:25173–82 [Google Scholar]
  8. Blankenship E, Vahedi-Faridi A, Lodowski DT. 8.  2015. The high-resolution structure of activated opsin reveals a conserved solvent network in the transmembrane region essential for activation. Structure 23:2358–64 [Google Scholar]
  9. Bogan AA, Thorn KS. 9.  1998. Anatomy of hot spots in protein interfaces. J. Mol. Biol. 280:1–9 [Google Scholar]
  10. Bönsch C, Munteanu M, Rossitto-Borlat I, Fürstenberg A, Hartley O. 10.  2015. Potent anti-HIV chemokine analogs direct post-endocytic sorting of CCR5. PLOS ONE 10:e0125396 [Google Scholar]
  11. Bradley ME, Bond ME, Manini J, Brown Z, Charlton SJ. 11.  2009. SB265610 is an allosteric, inverse agonist at the human CXCR2 receptor. Br. J. Pharmacol. 158:328–38 [Google Scholar]
  12. Brelot A, Heveker N, Montes M, Alizon M. 12.  2000. Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J. Biol. Chem. 275:23736–44 [Google Scholar]
  13. Brown GD, Shi Q, Delucca GV, Batt DG, Galella MA. 13.  et al. 2016. Discovery and synthesis of cyclohexenyl derivatives as modulators of CC chemokine receptor 2 activity. Bioorg. Med. Chem. Lett 26662–66 [Google Scholar]
  14. Buntinx M, Hermans B, Goossens J, Moechars D, Gilissen RAHJ. 14.  et al. 2008. Pharmacological profile of JNJ-27141491 [(S)-3-[3,4-Difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester], as a noncompetitive and orally active antagonist of the human chemokine receptor CCR2. J. Pharmacol. Exp. Ther 327:1–9 [Google Scholar]
  15. Burg JS, Ingram JR, Venkatakrishnan AJ, Jude KM, Dukkipati A. 15.  et al. 2015. Structural basis for chemokine recognition and activation of a viral G protein–coupled receptor. Science 347:1113–17 [Google Scholar]
  16. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R. 16.  et al. 2006. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med. 203:2201–13 [Google Scholar]
  17. Carter PH, Brown GD, Cherney RJ, Batt DG, Chen J. 17.  et al. 2015. Discovery of a potent and orally bioavailable dual antagonist of CC chemokine receptors 2 and 5. ACS Med. Chem. Lett 6439–44 [Google Scholar]
  18. Cerini F, Landay A, Gichinga C, Lederman MM, Flyckt R. 18.  et al. 2008. Chemokine analogues show suitable stability for development as microbicides. J. Acquir. Immune. Defic. Syndr. 49:472–76 [Google Scholar]
  19. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS. 19.  et al. 2007. High-resolution crystal structure of an engineered human β2-adrenergic G protein–coupled receptor. Science 318:1258–65 [Google Scholar]
  20. Colin P, Benureau Y, Staropoli I, Wang Y, Gonzalez N. 20.  et al. 2013. HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines. PNAS 110:9475–80 [Google Scholar]
  21. Cooke RM, Brown AJ, Marshall FH, Mason JS. 21.  2015. Structures of G protein–coupled receptors reveal new opportunities for drug discovery. Drug Discov. Today 20:1355–64 [Google Scholar]
  22. Copeland RA. 22.  2016. The drug-target residence time model: a 10-year retrospective. Nat. Rev. Drug Discov. 15:87–95 [Google Scholar]
  23. Couñago RM, Knapp KM, Nakatani Y, Fleming SB, Corbett M. 23.  et al. 2015. Structures of orf virus chemokine binding protein in complex with host chemokines reveal clues to broad binding specificity. Structure 23:1199–213 [Google Scholar]
  24. Crump MP, Gong JH, Loetscher P, Rajarathnam K, Amara A. 24.  et al. 1997. Solution structure and basis for functional activity of stromal cell–derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J 16:6996–7007 [Google Scholar]
  25. Dasse O, Evans J, Zhai H-X, Zou D, Kintigh J. 25.  et al. 2007. Novel, acidic CCR2 receptor antagonists: lead optimization. Lett. Drug Des. Discov. 4:263–71 [Google Scholar]
  26. De Clercq E. 26.  2010. Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil) and potential of other CXCR4 antagonists as stem cell mobilizers. Pharmacol. Ther. 128:509–18 [Google Scholar]
  27. de Kruijf P, van Heteren J, Lim HD, Conti PGM, van der Lee MMC. 27.  et al. 2009. Nonpeptidergic allosteric antagonists differentially bind to the CXCR2 chemokine receptor. J. Pharmacol. Exp. Ther. 329:783–90 [Google Scholar]
  28. de Mendonca FL, da Fonseca PCA, Phillips RM, Saldanha JW, Williams TJ, Pease JE. 28.  2005. Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist. J. Biol. Chem. 280:4808–16 [Google Scholar]
  29. Deupi X, Kobilka BK. 29.  2010. Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Physiology 25:293–303 [Google Scholar]
  30. DeVree BT, Mahoney JP, Vélez-Ruiz GA, Rasmussen SGF, Kuszak AJ. 30.  et al. 2016. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535:182–86 [Google Scholar]
  31. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B. 31.  et al. 2005. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother. 49:4721–32 [Google Scholar]
  32. Drury LJ, Ziarek JJ, Gravel SP, Veldkamp CT, Takekoshi T. 32.  et al. 2011. Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. PNAS 108:17655–60 [Google Scholar]
  33. Duvic M, Pinter-Brown LC, Foss FM, Sokol L, Jorgensen JL. 33.  et al. 2015. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 125:1883–89 [Google Scholar]
  34. Dyer DP, Salanga CL, Volkman BF, Kawamura T, Handel TM. 34.  2016. The dependence of chemokine–glycosaminoglycan interactions on chemokine oligomerization. Glycobiology 26:312–26 [Google Scholar]
  35. Eulberg D, Purschke W, Anders H-J, Selve N, Klussmann S. 35.  2008. Spiegelmer NOX-E36 for renal diseases. Therapeutic Oligonucleotides J Kurreck 200–25 Cambridge, UK: Royal Soc. Chem. [Google Scholar]
  36. Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG. 36.  1996. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274:768–70 [Google Scholar]
  37. Farzan M, Babcock GJ, Vasilieva N, Wright PL, Kiprilov E. 37.  et al. 2002. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1α association and HIV-1 entry. J. Biol. Chem. 277:29484–89 [Google Scholar]
  38. Feng Y, Broder CC, Kennedy PE, Berger EA. 38.  1996. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein–coupled receptor. Science 272:872–77 [Google Scholar]
  39. Gaertner H, Cerini F, Escola J-M, Kuenzi G, Melotti A. 39.  et al. 2008. Highly potent, fully recombinant anti-HIV chemokines: reengineering a low-cost microbicide. PNAS 105:17706–11 [Google Scholar]
  40. Gentry PR, Sexton PM, Christopoulos A. 40.  2015. Novel allosteric modulators of G protein–coupled receptors. J. Biol. Chem. 290:19478–88 [Google Scholar]
  41. Gerard C, Rollins BJ. 41.  2001. Chemokines and disease. Nat. Immunol. 2:108–15 [Google Scholar]
  42. Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. 42.  1997. Agonists induce conformational changes in transmembrane domains III and VI of the β2 adrenoceptor. EMBO J 16:6737–47 [Google Scholar]
  43. Goncalves JA, South K, Ahuja S, Zaitseva E, Opefi CA. 43.  et al. 2010. Highly conserved tyrosine stabilizes the active state of rhodopsin. PNAS 107:19861–66 [Google Scholar]
  44. Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I. 44.  1997. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J. Exp. Med. 186:131–37 [Google Scholar]
  45. Granier S, Kim S, Shafer AM, Ratnala VRP, Fung JJ. 45.  et al. 2007. Structure and conformational changes in the C-terminal domain of the β2-adrenoceptor: insights from fluorescence resonance energy transfer studies. J. Biol. Chem. 282:13895–905 [Google Scholar]
  46. Griffith JW, Sokol CL, Luster AD. 46.  2014. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32:659–702 [Google Scholar]
  47. Griffiths K, Dolezal O, Cao B, Nilsson SK, See HB. 47.  et al. 2016. I-bodies, human single domain antibodies that antagonize chemokine receptor CXCR4. J. Biol. Chem. 291:12641–57 [Google Scholar]
  48. Gustavsson M, Wang L, van Gils N, Stephens BS, Zhang P. 48.  et al. 2017. Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Common 8:14135–49 [Google Scholar]
  49. Haessler U, Pisano M, Wu M, Swartz MA. 49.  2011. Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. PNAS 108:5614–19 [Google Scholar]
  50. Hanes MS, Salanga CL, Chowdry AB, Comerford I, McColl SR. 50.  et al. 2015. Dual targeting of the chemokine receptors CXCR4 and ACKR3 with novel engineered chemokines. J. Biol. Chem. 290:22385–97 [Google Scholar]
  51. Hemmerich S, Paavola C, Bloom A, Bhakta S, Freedman R. 51.  et al. 1999. Identification of residues in the monocyte chemotactic protein-1 that contact the MCP-1 receptor, CCR2. Biochemistry 38:13013–25 [Google Scholar]
  52. Hino T, Arakawa T, Iwanari H, Yurugi-Kobayashi T, Ikeda-Suno C. 52.  et al. 2012. G-protein–coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature 482:237–40 [Google Scholar]
  53. Hoellenriegel J, Zboralski D, Maasch C, Rosin NY, Wierda WG. 53.  et al. 2014. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 123:1032–39 [Google Scholar]
  54. Horuk R. 54.  2009. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov. 8:23–33 [Google Scholar]
  55. Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN. 55.  et al. 2015. Structural insights into μ-opioid receptor activation. Nature 524:315–21 [Google Scholar]
  56. Jacobson JM, Lalezari JP, Thompson MA, Fichtenbaum CJ, Saag MS. 56.  et al. 2010. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob. Agents Chemother. 54:4137–42 [Google Scholar]
  57. Jahnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY. 57.  et al. 2010. CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. PNAS 107:20565–70 [Google Scholar]
  58. Jin H, Shen X, Baggett BR, Kong X, Li Wang PJ. 58.  2007. The human CC chemokine MIP-1β dimer is not competent to bind to the CCR5 receptor. J. Biol. Chem. 282:27976–83 [Google Scholar]
  59. Joseph PRB, Rajarathnam K. 59.  2015. Solution NMR characterization of WTCXCL8 monomer and dimer binding to CXCR1 N-terminal domain. Protein Sci 24:81–92 [Google Scholar]
  60. Kang Y, Zhou XE, Gao X, He Y, Liu W. 60.  et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523:561–67 [Google Scholar]
  61. Kashyap MK, Amaya-Chanaga CI, Kumar D, Choi MY, Rassenti LZ. 61.  et al. 2015. Targeting the CXCR4–CXCL12 pathway using an anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia. Blood 126:4162–62 [Google Scholar]
  62. Katancik JA, Sharma A, de Nardin E. 62.  2000. Interleukin 8, neutrophil-activating peptide-2 and GRO-α bind to and elicit cell activation via specific and different amino acid residues of CXCR2. Cytokine 12:1480–88 [Google Scholar]
  63. Katritch V, Cherezov V, Stevens RC. 63.  2012. Diversity and modularity of G protein–coupled receptor structures. Trends Pharmacol. Sci. 33:17–27 [Google Scholar]
  64. Katritch V, Cherezov V, Stevens RC. 64.  2013. Structure–function of the G protein–coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53:531–56 [Google Scholar]
  65. Katritch V, Rueda M, Abagyan R. 65.  2012. Ligand-guided receptor optimization. Methods Mol. Biol. 857:189–205 [Google Scholar]
  66. Kettle JG, Faull AW, Barker AJ, Davies DH, Stone MA. 66.  2004. N-benzylindole-2-carboxylic acids: potent functional antagonists of the CCR2b chemokine receptor. Bioorg. Med. Chem. Lett 14405–8 [Google Scholar]
  67. Kofuku Y, Yoshiura C, Ueda T, Terasawa H, Hirai T. 67.  et al. 2009. Structural basis of the interaction between chemokine stromal cell–derived factor-1/CXCL12 and its G-protein–coupled receptor CXCR4. J. Biol. Chem. 284:35240–50 [Google Scholar]
  68. Kufareva I. 68.  2016. Chemokines and their receptors: insights from molecular modeling and crystallography. Curr. Opin. Pharmacol. 30:27–37 [Google Scholar]
  69. Kufareva I, Salanga CL, Handel TM. 69.  2015. Chemokine and chemokine receptor structure and interactions: implications for therapeutic strategies. Immunol. Cell Biol. 93:372–83 [Google Scholar]
  70. Kufareva I, Stephens BS, Holden LG, Qin L, Zhao C. 70.  et al. 2014. Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: molecular modeling and experimental validation. PNAS 111:E5363–E72 [Google Scholar]
  71. Lamichhane R, Liu JJ, Pljevaljcic G, White KL, van der Schans E. 71.  et al. 2015. Single-molecule view of basal activity and activation mechanisms of the G protein-coupled receptor β2AR. PNAS 112:14254–59 [Google Scholar]
  72. Lau EK, Paavola CD, Johnson Z, Gaudry JP, Geretti E. 72.  et al. 2004. Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1: implications for structure and function in vivo. J. Biol. Chem. 279:22294–305 [Google Scholar]
  73. Lefrançois M, Lefebvre M-R, Saint-Onge G, Boulais PE, Lamothe S. 73.  et al. 2011. Agonists for the chemokine receptor CXCR4. ACS Med. Chem. Lett 2597–602 [Google Scholar]
  74. Liang WG, Triandafillou CG, Huang T-Y, Zulueta MML, Banerjee S. 74.  et al. 2016. Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3. PNAS 113:5000–5 [Google Scholar]
  75. Liu J, Louie S, Hsu W, Yu KM, Nicholas HB, Rosenquist GL. 75.  2008. Tyrosine sulfation is prevalent in human chemokine receptors important in lung disease. Am. J. Respir. Cell Mol. Biol. 38:738–43 [Google Scholar]
  76. Lubman OY, Fremont DH. 76.  2016. Parallel evolution of chemokine binding by structurally related herpesvirus decoy receptors. Structure 24:57–69 [Google Scholar]
  77. Ludeman JP, Stone MJ. 77.  2014. The structural role of receptor tyrosine sulfation in chemokine recognition. Br. J. Pharmacol. 171:1167–79 [Google Scholar]
  78. Lusti-Narasimhan M, Power CA, Allet B, Alouani S, Bacon KB. 78.  et al. 1995. Mutation of Leu25 and Val27 introduces CC chemokine activity into interleukin-8. J. Biol. Chem. 270:2716–21 [Google Scholar]
  79. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H. 79.  et al. 2004. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J. Virol. 78:8654–62 [Google Scholar]
  80. Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z. 80.  et al. 2015. Structural insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161:1101–11 [Google Scholar]
  81. Maussang D, Mujić-Delić A, Descamps FJ, Stortelers C, Vanlandschoot P. 81.  et al. 2013. Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo. J. Biol. Chem. 288:29562–72 [Google Scholar]
  82. Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H. 82.  et al. 1997. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91:385–95 [Google Scholar]
  83. Millard CJ, Ludeman JP, Canals M, Bridgford JL, Hinds M. 83.  et al. 2014. Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1. Structure 22:1571–81 [Google Scholar]
  84. Mirzadegan T, Benko G, Filipek S, Palczewski K. 84.  2003. Sequence analyses of G-protein–coupled receptors: similarities to rhodopsin. Biochemistry 42:2759–67 [Google Scholar]
  85. Monteclaro FS, Charo IF. 85.  1996. The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1α receptor, confers chemokine selectivity: evidence for a two-step mechanism for MCP-1 receptor activation. J. Biol. Chem. 271:19084–92 [Google Scholar]
  86. Montpas N, Cabana J, St-Onge G, Gravel S, Morin G. 86.  et al. 2015. Mode of binding of the cyclic agonist peptide TC14012 to CXCR7: identification of receptor and compound determinants. Biochemistry 54:1505–15 [Google Scholar]
  87. Muller A, Homey B, Soto H, Ge N, Catron D. 87.  et al. 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56 [Google Scholar]
  88. Muniz-Medina VM, Jones S, Maglich JM, Galardi C, Hollingsworth RE. 88.  et al. 2009. The relative activity of “function sparing” HIV-1 entry inhibitors on viral entry and CCR5 internalization: Is allosteric functional selectivity a valuable therapeutic property?. Mol. Pharmacol. 75:490–501 [Google Scholar]
  89. Murphy JW, Yuan H, Kong Y, Xiong Y, Lolis EJ. 89.  2010. Heterologous quaternary structure of CXCL12 and its relationship to the CC chemokine family. Proteins 78:1331–37 [Google Scholar]
  90. Mysinger MM, Weiss DR, Ziarek JJ, Gravel S, Doak AK. 90.  et al. 2012. Structure-based ligand discovery for the protein–protein interface of chemokine receptor CXCR4. PNAS 109:5517–22 [Google Scholar]
  91. Nasser MW, Raghuwanshi SK, Grant DJ, Jala VR, Rajarathnam K, Richardson RM. 91.  2009. Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. J. Immunol. 183:3425–32 [Google Scholar]
  92. Nibbs RJB, Graham GJ. 92.  2013. Immune regulation by atypical chemokine receptors. Nat. Rev. Immunol. 13:815–29 [Google Scholar]
  93. Nicholls DJ, Tomkinson NP, Wiley KE, Brammall A, Bowers L. 93.  et al. 2008. Identification of a putative intracellular allosteric antagonist binding-site in the CXC chemokine receptors 1 and 2. Mol. Pharmacol. 74:1193–202 [Google Scholar]
  94. Nijmeijer S, Leurs R, Smit MJ, Vischer HF. 94.  2010. The Epstein–Barr virus-encoded G protein–coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Gαi proteins, and constitutively impairs CXCR4 functioning. J. Biol. Chem. 285:29632–41 [Google Scholar]
  95. Oberthur D, Achenbach J, Gabdulkhakov A, Buchner K, Maasch C. 95.  et al. 2015. Crystal structure of a mirror-image l-RNA aptamer (Spiegelmer) in complex with the natural l-protein target CCL2. Nat. Commun. 6:6923 [Google Scholar]
  96. Oswald C, Rappas M, Kean J, Doré AS, Errey JC. 96.  et al. 2016. Intracellular allosteric antagonism of the CCR9 receptor. Nature 540:462–65 [Google Scholar]
  97. Paavola CD, Hemmerich S, Grunberger D, Polsky I, Bloom A. 97.  et al. 1998. Monomeric monocyte chemoattractant protein-1 (MCP-1) binds and activates the MCP-1 receptor CCR2B. J. Biol. Chem. 273:33157–65 [Google Scholar]
  98. Pakianathan DR, Kuta EG, Artis DR, Skelton NJ, Hebert CA. 98.  1997. Distinct but overlapping epitopes for the interaction of a CC-chemokine with CCR1, CCR3 and CCR5. Biochemistry 36:9642–48 [Google Scholar]
  99. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H. 99.  et al. 2000. Crystal structure of rhodopsin: a G protein–coupled receptor. Science 289:739–45 [Google Scholar]
  100. Peace S, Philp J, Brooks C, Piercy V, Moores K. 100.  et al. 2010. Identification of a sulfonamide series of CCR2 antagonists. Bioorg. Med. Chem. Lett 203961–64 [Google Scholar]
  101. Pease J, Horuk R. 101.  2012. Chemokine receptor antagonists. J. Med. Chem 559363–92 [Google Scholar]
  102. Proudfoot AEI, Power CA, Schwarz MK. 102.  2010. Anti-chemokine small molecule drugs: a promising future?. Expert Opin. Investig. Drugs 19:345–55 [Google Scholar]
  103. Proudfoot AEI. 103.  2002. Chemokine receptors: multifaceted therapeutic targets. Nat. Rev. Immunol. 2:106–15 [Google Scholar]
  104. Qin L, Kufareva I, Holden LG, Wang C, Zheng Y. 104.  et al. 2015. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science 347:1117–22 [Google Scholar]
  105. Rajagopal S, Kim J, Ahn S, Craig S, Lam CM. 105.  et al. 2010. β-arrestin- but not G protein–mediated signaling by the “decoy” receptor CXCR7. PNAS 107:628–32 [Google Scholar]
  106. Rajarathnam K, Sykes B, Kay C, Dewald B, Geiser T. 106.  et al. 1994. Neutrophil activation by monomeric interleukin-8. Science 264:90–92 [Google Scholar]
  107. Rapp C, Snow S, Laufer T, McClendon CL. 107.  2013. The role of tyrosine sulfation in the dimerization of the CXCR4:SDF-1 complex. Protein Sci 22:1025–36 [Google Scholar]
  108. Rasmussen SGF, Choi H-J, Fung JJ, Pardon E, Casarosa P. 108.  et al. 2011. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469:175–80 [Google Scholar]
  109. Rasmussen SGF, DeVree BT, Zou Y, Kruse AC, Chung KY. 109.  et al. 2011. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477:549–55 [Google Scholar]
  110. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS. 110.  et al. 2007. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318:1266–73 [Google Scholar]
  111. Rossi D, Zlotnik A. 111.  2000. The biology of chemokines and their receptors. Annu. Rev. Immunol. 18:217–42 [Google Scholar]
  112. Russo E, Teijeira A, Vaahtomeri K, Willrodt AH, Bloch JS. 112.  et al. 2016. Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels. Cell Rep 14:1723–34 [Google Scholar]
  113. Sabroe I, Peck MJ, Van Keulen BJ, Jorritsma A, Simmons G. 113.  et al. 2000. A small molecule antagonist of chemokine receptors CCR1 and CCR3: potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J. Biol. Chem. 275:25985–92 [Google Scholar]
  114. Salchow K, Bond ME, Evans SC, Press NJ, Charlton SJ. 114.  et al. 2010. A common intracellular allosteric binding site for antagonists of the CXCR2 receptor. Br. J. Pharmacol. 159:1429–39 [Google Scholar]
  115. Schall TJ, Proudfoot AEI. 115.  2011. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11:355–63 [Google Scholar]
  116. Scholten DJ, Canals M, Maussang D, Roumen L, Smit MJ. 116.  et al. 2011. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165:1617–43 [Google Scholar]
  117. Schwarz J, Sixt M. 117.  2016. Quantitative analysis of dendritic cell haptotaxis. Methods Enzymol 570:567–81 [Google Scholar]
  118. Sepuru KM, Rajarathnam K. 118.  2016. CXCL1/MGSA is a novel glycosaminoglycan (GAG)-binding chemokine: structural evidence for two distinct non-overlapping binding domains. J. Biol. Chem. 291:4247–55 [Google Scholar]
  119. Smith EW, Liu Y, Getschman AE, Peterson FC, Ziarek JJ. 119.  et al. 2014. Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine. J. Med. Chem 579693–99 [Google Scholar]
  120. Smith EW, Nevins AM, Qiao Z, Liu Y, Getschman AE. 120.  et al. 2016. Structure-based identification of novel ligands targeting multiple sites within a chemokine–G-protein-coupled-receptor interface. J. Med. Chem 594342–51 [Google Scholar]
  121. Solari R, Pease JE, Begg M. 121.  2015.. “ Chemokine receptors as therapeutic targets: Why aren't there more drugs?. Eur. J. Pharmacol. 746:363–67 [Google Scholar]
  122. Spiess K, Jeppesen MG, Malmgaard-Clausen M, Krzywkowski K, Dulal K. 122.  et al. 2015. Rationally designed chemokine-based toxin targeting the viral G protein–coupled receptor US28 potently inhibits cytomegalovirus infection in vivo. PNAS 112:8427–32 [Google Scholar]
  123. Springael J-Y, Le Minh PN, Urizar E, Costagliola S, Vassart G, Parmentier M. 123.  2006. Allosteric modulation of binding properties between units of chemokine receptor homo- and hetero-oligomers. Mol. Pharmacol. 69:1652–61 [Google Scholar]
  124. Staus DP, Strachan RT, Manglik A, Pani B, Kahsai AW. 124.  et al. 2016. Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein–coupled receptor activation. Nature 535:448–52 [Google Scholar]
  125. Steyaert J, Kobilka BK. 125.  2011. Nanobody stabilization of G protein–coupled receptor conformational states. Curr. Opin. Struct. Biol. 21:567–72 [Google Scholar]
  126. Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J. 126.  et al. 2001. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. PNAS 98:12718–23 [Google Scholar]
  127. Tamamura H, Omagari A, Oishi S, Kanamoto T, Yamamoto N. 127.  et al. 2000. Pharmacophore identification of a specific CXCR4 inhibitor, T140, leads to development of effective anti-HIV agents with very high selectivity indexes. Bioorg. Med. Chem. Lett 102633–37 [Google Scholar]
  128. Tamamura H, Xu Y, Hattori T, Zhang X, Arakaki R. 128.  et al. 1998. A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem. Biophys. Res. Commun. 253:877–82 [Google Scholar]
  129. Tan JHY, Canals M, Ludeman JP, Wedderburn J, Boston C. 129.  et al. 2012. Design and receptor interactions of obligate dimeric mutant of chemokine monocyte chemoattractant protein-1 (MCP-1). J. Biol. Chem. 287:14692–702 [Google Scholar]
  130. Tan JHY, Ludeman JP, Wedderburn J, Canals M, Hall P. 130.  et al. 2013. Tyrosine sulfation of chemokine receptor CCR2 enhances interactions with both monomeric and dimeric forms of the chemokine monocyte chemoattractant protein-1 (MCP-1). J. Biol. Chem. 288:10024–34 [Google Scholar]
  131. Tan Q, Zhu Y, Li J, Chen Z, Han GW. 131.  et al. 2013. Structure of the CCR5 chemokine receptor–HIV entry inhibitor maraviroc complex. Science 341:1387–90 [Google Scholar]
  132. Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T. 132.  et al. 2008. Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J. Med. Chem 517915–20 [Google Scholar]
  133. Tschammer N, Christopoulos A, Kenakin T. 133.  2015. Allosteric modulation of chemokine receptors. Chemokines N Tschammer 87–117 Basel, Switz. Springer [Google Scholar]
  134. Vauquelin G, Hall D, Charlton SJ. 134.  2015. ‘Partial’ competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models. Br. J. Pharmacol. 172:2300–15 [Google Scholar]
  135. Veillard NR, Kwak B, Pelli G, Mulhaupt F, James RW. 135.  et al. 2004. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ. Res. 94:253–61 [Google Scholar]
  136. Vela M, Aris M, Llorente M, Garcia-Sanz JA, Kremer L. 136.  2015. Chemokine receptor–specific antibodies in cancer immunotherapy: achievements and challenges. Front. Immunol. 6:12 [Google Scholar]
  137. Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC III. 137.  et al. 2008. Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci. Signal. 1:ra4 [Google Scholar]
  138. Veldkamp CT, Seibert C, Peterson FC, Sakmar TP, Volkman BF. 138.  2006. Recognition of a CXCR4 sulfotyrosine by the chemokine stromal cell–derived factor-1α (SDF-1α/CXCL12). J. Mol. Biol. 359:1400–9 [Google Scholar]
  139. Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T. 139.  et al. 2016. Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature 536:484–87 [Google Scholar]
  140. Vilums M, Zweemer AJM, Yu Z, de Vries H, Hillger JM. 140.  et al. 2013. Structure–kinetic relationships—an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. J. Med. Chem 567706–14 [Google Scholar]
  141. Watson C, Jenkinson S, Kazmierski W, Kenakin T. 141.  2005. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol. Pharmacol. 67:1268–82 [Google Scholar]
  142. Wescott MP, Kufareva I, Paes C, Goodman JR, Thaker Y. 142.  et al. 2016. Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices. PNAS 113:9928–33 [Google Scholar]
  143. Wu B, Chien EYT, Mol CD, Fenalti G, Liu W. 143.  et al. 2010. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330:1066–71 [Google Scholar]
  144. Xue X, Lu Q, Wei H, Wang D, Chen D. 144.  et al. 2011. Structural basis of chemokine sequestration by CrmD, a poxvirus-encoded tumor necrosis factor receptor. PLOS Pathog 7:e1002162 [Google Scholar]
  145. Yao XJ, Velez Ruiz G, Whorton MR, Rasmussen SGF, DeVree BT. 145.  et al. 2009. The effect of ligand efficacy on the formation and stability of a GPCR–G protein complex. PNAS 106:9501–6 [Google Scholar]
  146. Zhang M-Y, Lu J-J, Wang L, Gao Z-C, Hu H. 146.  et al. 2015. Development of monoclonal antibodies in China: overview and prospects. BioMed. Res. Int. 2015:10 [Google Scholar]
  147. Zhang W-B, Navenot J-M, Haribabu B, Tamamura H, Hiramatu K. 147.  et al. 2002. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J. Biol. Chem. 277:24515–21 [Google Scholar]
  148. Zheng Y, Qin L, Ortiz Zacarías NV, de Vries H, Han GW. 148.  et al. 2016. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:458–61 [Google Scholar]
  149. Zhong C, Wang J, Li B, Xiang H, Ultsch M. 149.  et al. 2013. Development and preclinical characterization of a humanized antibody targeting CXCL12. Clin. Cancer Res. 19:4433–45 [Google Scholar]
  150. Zhu JZ, Millard CJ, Ludeman JP, Simpson LS, Clayton DJ. 150.  et al. 2011. Tyrosine sulfation influences the chemokine binding selectivity of peptides derived from chemokine receptor CCR3. Biochemistry 50:1524–34 [Google Scholar]
  151. Ziarek JJ, Getschman AE, Butler SJ, Taleski D, Stephens B. 151.  et al. 2013. Sulfopeptide probes of the CXCR4/CXCL12 interface reveal oligomer-specific contacts and chemokine allostery. ACS Chem. Biol. 8:1955–63 [Google Scholar]
  152. Zweemer AJM, Bunnik J, Veenhuizen M, Miraglia F, Lenselink EB. 152.  et al. 2014. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2. Mol. Pharmacol. 86:358–68 [Google Scholar]
  153. Zweemer AJM, Nederpelt I, Vrieling H, Hafith S, Doornbos MLJ. 153.  et al. 2013. Multiple binding sites for small-molecule antagonists at the CC chemokine receptor 2. Mol. Pharmacol. 84:551–61 [Google Scholar]
/content/journals/10.1146/annurev-biophys-051013-022942
Loading
/content/journals/10.1146/annurev-biophys-051013-022942
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error