The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind cells to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally “undruggable” regions of membrane proteins, enabling modulation of protein–protein, protein–lipid, and protein–nucleic acid interactions. In this review, we survey the state of the art of high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets.


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Literature Cited

  1. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P. 1.  et al. 2015. Tissue-based map of the human proteome. Science 347:6220 [Google Scholar]
  2. Overington JP, Al-Lazikani B, Hopkins AL. 2.  2006. How many drug targets are there. ? Nat. Rev. Drug Discov. 5:993–96 [Google Scholar]
  3. Rask-Andersen M, Almén MS, Schiöth HB. 3.  2011. Trends in the exploitation of novel drug targets. Nat. Rev. Drug Discov. 10:579–90 [Google Scholar]
  4. Rask-Andersen M, Masuram S, Schiöth HB. 4.  2014. The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 54:9–26 [Google Scholar]
  5. Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P. 5.  et al. 2007. Structure-based maximal affinity model predicts small-molecule druggability. Nat. Biotechnol. 25:71–75 [Google Scholar]
  6. Lahti JL, Tang GW, Capriotti E, Liu T, Altman RB. 6.  2012. Bioinformatics and variability in drug response: a protein structural perspective. J. R. Soc. Interface 9:1409–37 [Google Scholar]
  7. Schenone M, Dančík V, Wagner BK, Clemons PA. 7.  2013. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol. 9:232–40 [Google Scholar]
  8. Wright PM, Seiple IB, Myers AG. 8.  2014. The evolving role of chemical synthesis in antibacterial drug discovery. Angew. Chem. Int. Ed. Engl. 53:8840–69 [Google Scholar]
  9. Yin H, Hamilton AD. 9.  2005. Strategies for targeting protein–protein interactions with synthetic agents. Angew. Chem. Int. Ed. Engl. 44:4130–63 [Google Scholar]
  10. Wells JA, McClendon CL. 10.  2007. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450:1001–9 [Google Scholar]
  11. Azzarito V, Long K, Murphy NS, Wilson AJ. 11.  2013. Inhibition of α-helix-mediated protein–protein interactions using designed molecules. Nat. Chem. 5:161–73 [Google Scholar]
  12. Lagerström MC, Schiöth HB. 12.  2008. Structural diversity of G protein–coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov. 7:339–57 [Google Scholar]
  13. Rosenbaum DM, Rasmussen SGF, Kobilka BK. 13.  2009. The structure and function of G-protein-coupled receptors. Nature 459:356–63 [Google Scholar]
  14. Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM. 14.  2013. Molecular signatures of G-protein-coupled receptors. Nature 494:185–94 [Google Scholar]
  15. Klabunde T, Hessler G. 15.  2002. Drug design strategies for targeting G-protein-coupled receptors. ChemBioChem 3:928–44 [Google Scholar]
  16. White SH.16.  2015. Membrane Proteins of Known 3D Structure http://blanco.biomol.uci.edu/mpstruc/ [Google Scholar]
  17. Bai X, McMullan G, Scheres SH. 17.  2014. How cryo-EM is revolutionizing structural biology. Trends Biochem. Sci. 40:49–57 [Google Scholar]
  18. Miao J, Ishikawa T, Robinson IK, Murnane MM. 18.  2015. Beyond crystallography: diffractive imaging using coherent X-ray light sources. Science 348:530–35 [Google Scholar]
  19. Miao Y, Cross TA. 19.  2013. Solid state NMR and protein–protein interactions in membranes. Curr. Opin. Struct. Biol. 23:919–28 [Google Scholar]
  20. Brown MS, Ye J, Rawson RB, Goldstein JL. 20.  2000. Regulated intramembrane proteolysis. Cell 100:391–98 [Google Scholar]
  21. Beel AJ, Sanders CR. 21.  2008. Substrate specificity of γ-secretase and other intramembrane proteases. Cell Mol. Life Sci. 65:1311–34 [Google Scholar]
  22. Munter L-M, Voigt P, Harmeier A, Kaden D, Gottschalk KE. 22.  et al. 2007. GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42. EMBO J. 26:1702–12 [Google Scholar]
  23. Godfroy JI, Roostan M, Moroz YS, Korendovych IV, Yin H. 23.  2012. Isolated Toll-like receptor transmembrane domains are capable of oligomerization. PLOS ONE 7:e48875 [Google Scholar]
  24. Langosch D, Scharnagl C, Steiner H, Lemberg MK. 24.  2015. Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics. Trends Biochem. Sci. 40:318–27 [Google Scholar]
  25. Sun L, Zhao L, Yang G, Yan C, Zhou R. 25.  et al. 2015. Structural basis of human γ-secretase assembly. PNAS 112:6003–8 [Google Scholar]
  26. Hong M, Zhang Y, Hu F. 26.  2012. Membrane protein structure and dynamics from NMR spectroscopy. Annu. Rev. Phys. Chem. 63:1–24 [Google Scholar]
  27. Freedberg DI, Selenko P. 27.  2014. Live cell NMR. Annu. Rev. Biophys. 43:171–92 [Google Scholar]
  28. Claasen B, Axmann M, Meinecke R, Meyer B. 28.  2005. Direct observation of ligand binding to membrane proteins in living cells by a saturation transfer double difference (STDD) NMR spectroscopy method shows a significantly higher affinity of integrin αIIbβ3 in native platelets than in liposomes. J. Am. Chem. Soc. 127:916–19 [Google Scholar]
  29. Mari S, Invernizzi C, Spitaleri A, Alberici L, Ghitti M. 29.  et al. 2010. 2D TR-NOESY experiments interrogate and rank ligand–receptor interactions in living human cancer cells. Angew. Chem. Int. Ed. Engl. 49:1071–74 [Google Scholar]
  30. Clackson T, Wells J. 30.  1995. A hot spot of binding energy in a hormone–receptor interface. Science 267:383–86 [Google Scholar]
  31. Walters RFS, DeGrado WF. 31.  2006. Helix-packing motifs in membrane proteins. PNAS 103:13658–63 [Google Scholar]
  32. Moore DT, Berger BW, DeGrado WF. 32.  2008. Protein–protein interactions in the membrane: sequence, structural, and biological motifs. Structure 16:991–1001 [Google Scholar]
  33. Matthews EE, Zoonens M, Engelman DM. 33.  2006. Dynamic helix interactions in transmembrane signaling. Cell 127:447–50 [Google Scholar]
  34. Fink A, Sal-Man N, Gerber D, Shai Y. 34.  2012. Transmembrane domains interactions within the membrane milieu: principles, advances and challenges. Biochim. Biophys. Acta 1818:974–83 [Google Scholar]
  35. Stangl M, Schneider D. 35.  2015. Functional competition within a membrane: lipid recognition vs. transmembrane helix oligomerization. Biochim. Biophys. Acta 1848:1886–96 [Google Scholar]
  36. Senes A, Ubarretxena-Belandia I, Engelman DM. 36.  2001. The Cα–H⋅⋅⋅O hydrogen bond: a determinant of stability and specificity in transmembrane helix interactions. PNAS 98:9056–61 [Google Scholar]
  37. Senes A, Chadi DC, Law PB, Walters RFS, Nanda V, Degrado WF. 37.  2007. Ez, a depth-dependent potential for assessing the energies of insertion of amino acid side-chains into membranes: derivation and applications to determining the orientation of transmembrane and interfacial helices. J. Mol. Biol. 366:436–48 [Google Scholar]
  38. Kim S, Jeon T-J, Oberai A, Yang D, Schmidt JJ, Bowie JU. 38.  2005. Transmembrane glycine zippers: physiological and pathological roles in membrane proteins. PNAS 102:14278–83 [Google Scholar]
  39. Gurezka R, Laage R, Brosig B, Langosch D. 39.  1999. A heptad motif of leucine residues found in membrane proteins can drive self-assembly of artificial transmembrane segments. J. Biol. Chem. 274:9265–70 [Google Scholar]
  40. Furthmayr H, Marchesi VT. 40.  1976. Subunit structure of human erythrocyte glycophorin A. Biochemistry 15:1137–44 [Google Scholar]
  41. Furthmayr H, Galardy RE, Tomita M, Marchesi VT. 41.  1978. The intramembranous segment of human erythrocyte glycophorin A. Arch. Biochem. Biophys. 185:21–29 [Google Scholar]
  42. Manolios N, Bonifacino J, Klausner R. 42.  1990. Transmembrane helical interactions and the assembly of the T cell receptor complex. Science 249:274–77 [Google Scholar]
  43. Brosig B, Langosch D. 43.  1998. The dimerization motif of the glycophorin A transmembrane segment in membranes: importance of glycine residues. Protein Sci. 7:1052–56 [Google Scholar]
  44. Lemmon MA, Flanagan JM, Hunt JF, Adair BD, Bormann BJ. 44.  et al. 1992. Glycophorin A dimerization is driven by specific interactions between transmembrane α-helices. J. Biol. Chem. 267:7683–89 [Google Scholar]
  45. Adams PD, Engelman DM, Brünger AT. 45.  1996. Improved prediction for the structure of the dimeric transmembrane domain of glycophorin A obtained through global searching. Proteins 26:257–61 [Google Scholar]
  46. Langosch D, Brosig B, Kolmar H, Fritz HJ. 46.  1996. Dimerisation of the glycophorin A transmembrane segment in membranes probed with the ToxR transcription activator. J. Mol. Biol. 263:525–30 [Google Scholar]
  47. MacKenzie KR.47.  1997. A transmembrane helix dimer: structure and implications. Science 276:131–33 [Google Scholar]
  48. Russ WP, Engelman DM. 48.  2000. The GxxxG motif: a framework for transmembrane helix–helix association. J. Mol. Biol. 296:911–19 [Google Scholar]
  49. Ridder A, Skupjen P, Unterreitmeier S, Langosch D. 49.  2005. Tryptophan supports interaction of transmembrane helices. J. Mol. Biol. 354:894–902 [Google Scholar]
  50. Lin S-C, Lo Y-C, Wu H. 50.  2010. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature 465:885–90 [Google Scholar]
  51. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM. 51.  et al. 2007. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–82 [Google Scholar]
  52. Kang JY, Nan X, Jin MS, Youn S-J, Ryu YH. 52.  et al. 2009. Recognition of lipopeptide patterns by Toll-like receptor 2–Toll-like receptor 6 heterodimer. Immunity 31:873–84 [Google Scholar]
  53. Kim HM, Park BS, Kim J-I, Kim SE, Lee J. 53.  et al. 2007. Crystal structure of the TLR4–MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–17 [Google Scholar]
  54. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J. 54.  et al. 2008. Structural basis of Toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–81 [Google Scholar]
  55. Yoon S, Kurnasov O, Natarajan V, Hong M, Gudkov AV. 55.  et al. 2012. Structural basis of TLR5–flagellin recognition and signaling. Science 335:859–64 [Google Scholar]
  56. Tanji H, Ohto U, Shibata T, Miyake K, Shimizu T. 56.  2013. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science 339:1426–29 [Google Scholar]
  57. Ohto U, Shibata T, Tanji H, Ishida H, Krayukhina E. 57.  et al. 2015. Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature 520:702–5 [Google Scholar]
  58. Yoon S, Hong M, Wilson IA. 58.  2011. An unusual dimeric structure and assembly for TLR4 regulator RP105–MD-1. Nat. Struct. Mol. Biol. 18:1028–35 [Google Scholar]
  59. Ohto U, Miyake K, Shimizu T. 59.  2011. Crystal structures of mouse and human RP105/MD-1 complexes reveal unique dimer organization of the Toll-like receptor family. J. Mol. Biol. 413:815–25 [Google Scholar]
  60. Nishiya T, DeFranco AL. 60.  2004. Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors. J. Biol. Chem. 279:19008–17 [Google Scholar]
  61. Panter G, Jerala R. 61.  2011. The ectodomain of the Toll-like receptor 4 prevents constitutive receptor activation. J. Biol. Chem. 286:23334–44 [Google Scholar]
  62. Van den Bogaart G, Meyenberg K, Risselada HJ, Amin H, Willig KI. 62.  et al. 2011. Membrane protein sequestering by ionic protein–lipid interactions. Nature 479:552–55 [Google Scholar]
  63. Aimon S, Callan-Jones A, Berthaud A, Pinot M, Toombes GES, Bassereau P. 63.  2014. Membrane shape modulates transmembrane protein distribution. Dev. Cell 28:212–18 [Google Scholar]
  64. Lingwood D, Simons K. 64.  2010. Lipid rafts as a membrane-organizing principle. Science 327:46–50 [Google Scholar]
  65. Yang H, Chen Y-Z, Zhang Y, Wang X, Zhao X. 65.  et al. 2015. A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nat. Commun. 6:5717 [Google Scholar]
  66. Neumann B, Coakley S, Giordano-Santini R, Linton C, Lee ES. 66.  et al. 2015. EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517:219–22 [Google Scholar]
  67. McMahon HT, Gallop JL. 67.  2005. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438:590–96 [Google Scholar]
  68. Drin G, Casella J-F, Gautier R, Boehmer T, Schwartz TU, Antonny B. 68.  2007. A general amphipathic α-helical motif for sensing membrane curvature. Nat. Struct. Mol. Biol. 14:138–46 [Google Scholar]
  69. Antonny B.69.  2011. Mechanisms of membrane curvature sensing. Annu. Rev. Biochem. 80:101–23 [Google Scholar]
  70. Colombo M, Raposo G, Théry C. 70.  2014. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30:255–89 [Google Scholar]
  71. Kastelowitz N, Yin H. 71.  2014. Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes. ChemBioChem 15:923–28 [Google Scholar]
  72. Subra C, Laulagnier K, Perret B, Record M. 72.  2007. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89:205–12 [Google Scholar]
  73. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L. 73.  et al. 2008. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10:1470–76 [Google Scholar]
  74. Shen B, Wu N, Yang J-M, Gould SJ. 74.  2011. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J. Biol. Chem. 286:14383–95 [Google Scholar]
  75. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J. 75.  et al. 2013. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4:2980 [Google Scholar]
  76. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C. 76.  et al. 1998. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat. Med. 4:594–600 [Google Scholar]
  77. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R. 77.  et al. 2015. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161:1046–57 [Google Scholar]
  78. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST. 78.  et al. 2015. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:177–82 [Google Scholar]
  79. Gallop JL, Jao CC, Kent HM, Butler PJG, Evans PR. 79.  et al. 2006. Mechanism of endophilin N-BAR domain–mediated membrane curvature. EMBO J. 25:2898–910 [Google Scholar]
  80. Hui E, Johnson CP, Yao J, Dunning FM, Chapman ER. 80.  2009. Synaptotagmin-mediated bending of the target membrane is a critical step in Ca2+-regulated fusion. Cell 138:709–21 [Google Scholar]
  81. Isas JM, Ambroso MR, Hegde PB, Langen J, Langen R. 81.  2015. Tubulation by amphiphysin requires concentration-dependent switching from wedging to scaffolding. Structure 23:873–81 [Google Scholar]
  82. Zurek N, Sparks L, Voeltz G. 82.  2011. Reticulon short hairpin transmembrane domains are used to shape ER tubules. Traffic 12:28–41 [Google Scholar]
  83. Westrate LM, Lee JE, Prinz WA, Voeltz GK. 83.  2015. Form follows function: the importance of endoplasmic reticulum shape. Annu. Rev. Biochem. 84:791–811 [Google Scholar]
  84. Phillips R, Ursell T, Wiggins P, Sens P. 84.  2009. Emerging roles for lipids in shaping membrane-protein function. Nature 459:379–85 [Google Scholar]
  85. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C. 85.  et al. 2007. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13:1050–59 [Google Scholar]
  86. Round JL, Lee SM, Li J, Tran G, Jabri B. 86.  et al. 2011. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–77 [Google Scholar]
  87. Mukherji A, Kobiita A, Ye T, Chambon P. 87.  2013. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153:812–27 [Google Scholar]
  88. Hennessy EJ, Parker AE, O'Neill LAJ. 88.  2010. Targeting Toll-like receptors: emerging therapeutics. ? Nat. Rev. Drug Discov. 9:293–307 [Google Scholar]
  89. Wang X, Smith C, Yin H. 89.  2013. Targeting Toll-like receptors with small molecule agents. Chem. Soc. Rev. 42:4859–66 [Google Scholar]
  90. Hoque R, Farooq A, Malik A, Trawick BN, Berberich DW. 90.  et al. 2013. A novel small-molecule enantiomeric analogue of traditional (−)-morphinans has specific TLR9 antagonist properties and reduces sterile inflammation-induced organ damage. J. Immunol. 190:4297–4304 [Google Scholar]
  91. Köberlin MS, Snijder B, Heinz LX, Baumann CL, Fauster A. 91.  et al. 2015. A conserved circular network of coregulated lipids modulates innate immune responses. Cell 162:170–83 [Google Scholar]
  92. Russ WP, Engelman DM. 92.  1999. TOXCAT: a measure of transmembrane helix association in a biological membrane. PNAS 96:863–68 [Google Scholar]
  93. Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Crémel G. 93.  et al. 2008. Transmembrane domain interactions control biological functions of neuropilin-1. Mol. Biol. Cell 19:646–54 [Google Scholar]
  94. Joce C, Wiener AA, Yin H. 94.  2011. Multi-Tox: application of the ToxR-transcriptional reporter assay to the study of multi-pass protein transmembrane domain oligomerization. Biochim. Biophys. Acta 1808:2948–53 [Google Scholar]
  95. Cromm PM, Spiegel J, Grossmann TN. 95.  2015. Hydrocarbon stapled peptides as modulators of biological function. ACS Chem. Biol. 10:1362–75 [Google Scholar]
  96. London N, Movshovitz-Attias D, Schueler-Furman O. 96.  2010. The structural basis of peptide–protein binding strategies. Structure 18:188–99 [Google Scholar]
  97. Bhosale S, Sisson AL, Talukdar P, Fürstenberg A, Banerji N. 97.  et al. 2006. Photoproduction of proton gradients with π-stacked fluorophore scaffolds in lipid bilayers. Science 313:84–86 [Google Scholar]
  98. Yin H, Slusky JS, Berger BW, Walters RS, Vilaire G. 98.  et al. 2007. Computational design of peptides that target transmembrane helices. Science 315:1817–22 [Google Scholar]
  99. Caputo GA, Litvinov RI, Li W, Bennett JS, Degrado WF, Yin H. 99.  2008. Computationally designed peptide inhibitors of protein–protein interactions in membranes. Biochemistry 47:8600–6 [Google Scholar]
  100. Wang Y, Barth P. 100.  2015. Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy. Nat. Commun. 6:7196 [Google Scholar]
  101. Shoichet BK, Kobilka BK. 101.  2012. Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol. Sci. 33:268–72 [Google Scholar]
  102. Lounkine E, Keiser MJ, Whitebread S, Mikhailov D, Hamon J. 102.  et al. 2012. Large-scale prediction and testing of drug activity on side-effect targets. Nature 486:361–67 [Google Scholar]
  103. Harvey AL, Edrada-Ebel R, Quinn RJ. 103.  2015. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14:111–29 [Google Scholar]
  104. Cheng K, Wang X, Yin H. 104.  2011. Small-molecule inhibitors of the TLR3/dsRNA complex. J. Am. Chem. Soc. 133:3764–67 [Google Scholar]
  105. Zhang S, Cheng K, Wang X, Yin H. 105.  2012. Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors. Bioorg. Med. Chem. 20:6073–79 [Google Scholar]
  106. Cheng K, Wang X, Zhang S, Yin H. 106.  2012. Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angew. Chem. 124:12412–15 [Google Scholar]
  107. Wang X, Saludes JP, Zhao TX, Csakai A, Fiorini Z. 107.  et al. 2012. Targeting the lateral interactions of transmembrane domain 5 of Epstein–Barr virus latent membrane protein 1. Biochim. Biophys. Acta 1818:2282–89 [Google Scholar]
  108. Takemura N, Kawasaki T, Kunisawa J, Sato S, Lamichhane A. 108.  et al. 2014. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat. Commun. 5:3492 [Google Scholar]
  109. Kim C, Ho D-H, Suk J-E, You S, Michael S. 109.  et al. 2013. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4:1562 [Google Scholar]
  110. Daniele SG, Béraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA. 110.  2015. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal. 8:ra45 [Google Scholar]
  111. Cheng K, Gao M, Godfroy JI, Brown PN, Kastelowitz N, Yin H. 111.  2015. Specific activation of the TLR1–TLR2 heterodimer by small-molecule agonists. Sci. Adv. 1:e1400139 [Google Scholar]
  112. Sammond DW, Joce C, Takeshita R, McQuate SE, Ghosh N. 112.  et al. 2011. Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1. Biopolymers 95:772–84 [Google Scholar]
  113. Young LS, Rickinson AB. 113.  2004. Epstein–Barr virus: 40 years on. Nat. Rev. Cancer 4:757–68 [Google Scholar]
  114. Küppers R.114.  2005. Mechanisms of B cell lymphoma pathogenesis. Nat. Rev. Cancer 5:251–62 [Google Scholar]
  115. Talbert-Slagle K, DiMaio D. 115.  2009. The bovine papillomavirus E5 protein and the PDGF β receptor: It takes two to tango. Virology 384:345–51 [Google Scholar]
  116. Freeman-Cook LL, Dixon AM, Frank JB, Xia Y, Ely L. 116.  et al. 2004. Selection and characterization of small random transmembrane proteins that bind and activate the platelet-derived growth factor β receptor. J. Mol. Biol. 338:907–20 [Google Scholar]
  117. Cammett TJ, Jun SJ, Cohen EB, Barrera FN, Engelman DM, Dimaio D. 117.  2010. Construction and genetic selection of small transmembrane proteins that activate the human erythropoietin receptor. PNAS 107:3447–52 [Google Scholar]
  118. Scheideman EH, Marlatt SA, Xie Y, Hu Y, Sutton RE, DiMaio D. 118.  2012. Transmembrane protein aptamers that inhibit CCR5 expression and HIV coreceptor function. J. Virol. 86:10281–92 [Google Scholar]
  119. Tinberg CE, Khare SD, Dou J, Doyle L, Nelson JW. 119.  et al. 2013. Computational design of ligand-binding proteins with high affinity and selectivity. Nature 501:212–16 [Google Scholar]
  120. Samish I, MacDermaid CM, Perez-Aguilar JM, Saven JG. 120.  2011. Theoretical and computational protein design. Annu. Rev. Phys. Chem. 62:129–49 [Google Scholar]
  121. Chaires JB.121.  2008. Calorimetry and thermodynamics in drug design. Annu. Rev. Biophys. 37:135–51 [Google Scholar]
  122. Saludes JP, Morton LA, Ghosh N, Beninson LA, Chapman ER. 122.  et al. 2012. Detection of highly curved membrane surfaces using a cyclic peptide derived from synaptotagmin-I. ACS Chem. Biol. 7:1629–35 [Google Scholar]
  123. Saludes JP, Morton LA, Coulup SK, Fiorini Z, Cook BM. 123.  et al. 2013. Multivalency amplifies the selection and affinity of bradykinin-derived peptides for lipid nanovesicles. Mol. Biosyst. 9:2005–9 [Google Scholar]
  124. Morton LA, Yang H, Saludes JP, Fiorini Z, Beninson L. 124.  et al. 2013. MARCKS-ED peptide as a curvature and lipid sensor. ACS Chem. Biol. 8:218–25 [Google Scholar]
  125. Zhao L, Lu W. 125.  2014. Mirror image proteins. Curr. Opin. Chem. Biol. 22:56–61 [Google Scholar]
  126. Kritzer JA, Stephens OM, Guarracino DA, Reznik SK, Schepartz A. 126.  2005. β-Peptides as inhibitors of protein–protein interactions. Bioorg. Med. Chem. 13:11–16 [Google Scholar]
  127. Horne WS, Gellman SH. 127.  2008. Foldamers with heterogeneous backbones. Acc. Chem. Res. 41:1399–408 [Google Scholar]
  128. Werle M, Bernkop-Schnürch A. 128.  2006. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 30:351–67 [Google Scholar]
  129. Haswell ES, Phillips R, Rees DC. 129.  2011. Mechanosensitive channels: What can they do and how do they do it. ? Structure 19:1356–69 [Google Scholar]
  130. Kralj JM, Douglass AD, Hochbaum DR, Maclaurin D, Cohen AE. 130.  2012. Optical recording of action potentials in mammalian neurons using a microbial rhodopsin. Nat. Methods 9:90–95 [Google Scholar]
  131. Manolios N, Collier S, Taylor J, Pollard J, Harrison LC, Bender V. 131.  1997. T cell antigen receptor transmembrane peptides modulate T cell function and T cell–mediated disease. Nat. Med. 3:84–88 [Google Scholar]
  132. Huynh NT, Ffrench RA, Boadle RA, Manolios N. 132.  2003. Transmembrane T-cell receptor peptides inhibit B- and natural killer–cell function. Immunology 108:458–64 [Google Scholar]
  133. Hebert TE, Moffett S, Morello J-P, Loisel TP, Bichet DG. 133.  et al. 1996. A peptide derived from a β2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem. 271:16384–92 [Google Scholar]
  134. Ng GY, O'Dowd BF, Lee SP, Chung HT, Brann MR. 134.  et al. 1996. Dopamine D2 receptor dimers and receptor-blocking peptides. Biochem. Biophys. Res. Commun. 227:200–4 [Google Scholar]
  135. Tarasova NI, Rice WG, Michejda CJ. 135.  1999. Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions. J. Biol. Chem. 274:34911–15 [Google Scholar]
  136. McDonnell JM, Beavil AJ, Mackay GA, Jameson BA, Korngold R. 136.  et al. 1996. Structure based design and characterization of peptides that inhibit IgE binding to its high-affinity receptor. Nat. Struct. Biol. 3:419–26 [Google Scholar]
  137. Shandler SJ, Korendovych IV, Moore DT, Smith-Dupont KB, Streu CN. 137.  et al. 2011. Computational design of a β-peptide that targets transmembrane helices. J. Am. Chem. Soc. 133:12378–81 [Google Scholar]
  138. Lemmon MA, Schlessinger J. 138.  2010. Cell signaling by receptor tyrosine kinases. Cell 141:1117–34 [Google Scholar]
  139. Mendrola JM, Berger MB, King MC, Lemmon MA. 139.  2002. The single transmembrane domains of ErbB receptors self-associate in cell membranes. J. Biol. Chem. 277:4704–12 [Google Scholar]
  140. Bennasroune A, Fickova M, Gardin A, Dirrig-Grosch S, Aunis D. 140.  et al. 2004. Transmembrane peptides as inhibitors of ErbB receptor signaling. Mol. Biol. Cell 15:3464–74 [Google Scholar]
  141. Lee J, Miyazaki M, Romeo GR, Shoelson SE. 141.  2014. Insulin receptor activation with transmembrane domain ligands. J. Biol. Chem. 289:19769–77 [Google Scholar]
  142. Fink A, Reuven EM, Arnusch CJ, Shmuel-Galia L, Antonovsky N, Shai Y. 142.  2013. Assembly of the TLR2/6 transmembrane domains is essential for activation and is a target for prevention of sepsis. J. Immunol. 190:6410–22 [Google Scholar]
  143. McLaughlin S, Murray D. 143.  2005. Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438:605–11 [Google Scholar]
  144. Kim J, Blackshear PJ, Johnson JD, McLaughlin S. 144.  1994. Phosphorylation reverses the membrane association of peptides that correspond to the basic domains of MARCKS and neuromodulin. Biophys. J. 67:227–37 [Google Scholar]
  145. Kim J, Shishido T, Jiang X, Aderem A, McLaughlin S. 145.  1994. Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles. J. Biol. Chem. 269:28214–19 [Google Scholar]
  146. Rauch ME, Ferguson CG, Prestwich GD, Cafiso DS. 146.  2002. Myristoylated alanine-rich C kinase substrate (MARCKS) sequesters spin-labeled phosphatidylinositol 4,5-bisphosphate in lipid bilayers. J. Biol. Chem. 277:14068–76 [Google Scholar]
  147. Zhang W, Crocker E, McLaughlin S, Smith SO. 147.  2003. Binding of peptides with basic and aromatic residues to bilayer membranes: Phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer. J. Biol. Chem. 278:21459–66 [Google Scholar]
  148. Wang J, Gambhir A, Hangyás-Mihályné G, Murray D, Golebiewska U, McLaughlin S. 148.  2002. Lateral sequestration of phosphatidylinositol 4,5-bisphosphate by the basic effector domain of myristoylated alanine-rich C kinase substrate is due to nonspecific electrostatic interactions. J. Biol. Chem. 277:34401–12 [Google Scholar]
  149. Vanni S, Hirose H, Barelli H, Antonny B, Gautier R. 149.  2014. A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment. Nat. Commun. 5:4916 [Google Scholar]
  150. Morton LA, Tamura R, de Jesus AJ, Espinoza A, Yin H. 150.  2014. Biophysical investigations with MARCKS-ED: dissecting the molecular mechanism of its curvature sensing behaviors. Biochim. Biophys. Acta 1838:3137–44 [Google Scholar]
  151. Yan L, de Jesus AJ, Tamura R, Li V, Cheng K, Yin H. 151.  2015. Curvature sensing MARCKS-ED peptides bind to membranes in a stereo-independent manner. J. Pept. Sci. 21:577–85 [Google Scholar]
  152. Lu H.152.  2014. TLR agonists for cancer immunotherapy: tipping the balance between the immune stimulatory and inhibitory effects. Front. Immunol. 5:83 [Google Scholar]
  153. Cheng K, Wang X, Zhang S, Yin H. 153.  2012. Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angew. Chem. Int. Ed. Engl. 51:12246–49 [Google Scholar]
  154. Schreiber SL, Kotz JD, Li M, Aubé J, Austin CP. 154.  et al. 2015. Advancing biological understanding and therapeutics discovery with small-molecule probes. Cell 161:1252–65 [Google Scholar]
  155. Yin H.155.  2008. Exogenous agents that target transmembrane domains of proteins. Angew. Chem. Int. Ed. Engl. 47:2744–52 [Google Scholar]

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