1932

Abstract

Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABARs) and G protein–coupled receptors (GPCRs). GABARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR–G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR–G protein selectivity, how accessory membrane proteins alter receptor–ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010919-023545
2020-01-06
2024-10-05
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/60/1/annurev-pharmtox-010919-023545.html?itemId=/content/journals/10.1146/annurev-pharmtox-010919-023545&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Almen MS, Nordstrom KJ, Fredriksson R, Schioth HB 2009. Mapping the human membrane proteome: A majority of the human membrane proteins can be classified according to function and evolutionary origin. BMC Biol 7:50
    [Google Scholar]
  2. 2. 
    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC et al. 2001. Initial sequencing and analysis of the human genome. Nature 409:860–921
    [Google Scholar]
  3. 3. 
    Overington JP, Al-Lazikani B, Hopkins AL 2006. How many drug targets are there?. Nat. Rev. Drug Discov. 5:993–96
    [Google Scholar]
  4. 4. 
    Sledz P, Caflisch A. 2018. Protein structure-based drug design: from docking to molecular dynamics. Curr. Opin. Struct. Biol. 48:93–102
    [Google Scholar]
  5. 5. 
    Bai XC, Yan C, Yang G, Lu P, Ma D et al. 2015. An atomic structure of human γ-secretase. Nature 525:212–17
    [Google Scholar]
  6. 6. 
    Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH 2015. Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife 4:e11182
    [Google Scholar]
  7. 7. 
    Liu F, Zhang Z, Csanady L, Gadsby DC, Chen J 2017. Molecular structure of the human CFTR ion channel. Cell 169:85–95.e8
    [Google Scholar]
  8. 8. 
    Zhang Z, Chen J. 2016. Atomic structure of the cystic fibrosis transmembrane conductance regulator. Cell 167:1586–97.e9
    [Google Scholar]
  9. 9. 
    Wang W, MacKinnon R. 2017. Cryo-EM structure of the open human ether-a-go-go-related K+ channel hERG. Cell 169:422–30.e10
    [Google Scholar]
  10. 10. 
    Shen H, Liu D, Wu K, Lei J, Yan N 2019. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science 363:1303–8
    [Google Scholar]
  11. 11. 
    Vandenberg JI, Perozo E, Allen TW 2017. Towards a structural view of drug binding to hERG K+ channels. Trends Pharmacol. Sci. 38:899–907
    [Google Scholar]
  12. 12. 
    Lau C, Hunter MJ, Stewart A, Perozo E, Vandenberg JI 2018. Never at rest: insights into the conformational dynamics of ion channels from cryo-electron microscopy. J. Physiol. 596:1107–19
    [Google Scholar]
  13. 13. 
    Shimada I, Ueda T, Kofuku Y, Eddy MT, Wuthrich K 2019. GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures. Nat. Rev. Drug Discov. 18:59–82
    [Google Scholar]
  14. 14. 
    Zhou XE, Melcher K, Xu HE 2019. Structural biology of G protein-coupled receptor signaling complexes. Protein Sci 28:487–501
    [Google Scholar]
  15. 15. 
    Thal DM, Glukhova A, Sexton PM, Christopoulos A 2018. Structural insights into G-protein-coupled receptor allostery. Nature 559:45–53
    [Google Scholar]
  16. 16. 
    Glukhova A, Draper-Joyce CJ, Sunahara RK, Arthur Christopoulos, Wotten D, Sexton PM 2018. Rules of engagement: GPCRs and G proteins. ACS Pharmacol. Trans. Sci. 1:73–142
    [Google Scholar]
  17. 17. 
    García-Nafría J, Tate CG. 2019. Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Mol. Cell. Endocrinol. 488:1–13
    [Google Scholar]
  18. 18. 
    Vinothkumar KR, Henderson R. 2016. Single particle electron cryomicroscopy: trends, issues and future perspective. Q. Rev. Biophys. 49:e13
    [Google Scholar]
  19. 19. 
    Passmore LA, Russo CJ. 2016. Specimen preparation for high-resolution cryo-EM. Methods Enzymol 579:51–86
    [Google Scholar]
  20. 20. 
    Cheng Y. 2015. Single-particle cryo-EM at crystallographic resolution. Cell 161:450–57
    [Google Scholar]
  21. 21. 
    Fernandez-Leiro R, Scheres SH. 2016. Unravelling biological macromolecules with cryo-electron microscopy. Nature 537:339–46
    [Google Scholar]
  22. 22. 
    Renaud JP, Chari A, Ciferri C, Liu WT, Remigy HW et al. 2018. Cryo-EM in drug discovery: achievements, limitations and prospects. Nat. Rev. Drug Discov. 17:471–92
    [Google Scholar]
  23. 23. 
    Scapin G, Potter CS, Carragher B 2018. Cryo-EM for small molecules discovery, design, understanding, and application. Cell Chem. Biol. 25:1318–25
    [Google Scholar]
  24. 24. 
    Merino F, Raunser S. 2017. Electron cryo-microscopy as a tool for structure-based drug development. Angew. Chem. Int. Ed. 56:2846–60
    [Google Scholar]
  25. 25. 
    Boland A, Chang L, Barford D 2017. The potential of cryo-electron microscopy for structure-based drug design. Essays Biochem 61:543–60
    [Google Scholar]
  26. 26. 
    Subramaniam S, Earl LA, Falconieri V, Milne JL, Egelman EH 2016. Resolution advances in cryo-EM enable application to drug discovery. Curr. Opin. Struct. Biol. 41:194–202
    [Google Scholar]
  27. 27. 
    Kuhlbrandt W. 2014. The resolution revolution. Science 343:1443–44
    [Google Scholar]
  28. 28. 
    Tate CG. 2010. Practical considerations of membrane protein instability during purification and crystallisation. Methods Mol. Biol. 601:187–203
    [Google Scholar]
  29. 29. 
    Liao M, Cao E, Julius D, Cheng Y 2014. Single particle electron cryo-microscopy of a mammalian ion channel. Curr. Opin. Struct. Biol. 27:1–7
    [Google Scholar]
  30. 30. 
    Campbell MG, Cheng A, Brilot AF, Moeller A, Lyumkis D et al. 2012. Movies of ice-embedded particles enhance resolution in electron cryo-microscopy. Structure 20:1823–28
    [Google Scholar]
  31. 31. 
    Scheres SH. 2014. Beam-induced motion correction for sub-megadalton cryo-EM particles. eLife 3:e03665
    [Google Scholar]
  32. 32. 
    Ripstein ZA, Rubinstein JL. 2016. Processing of cryo-EM movie data. Methods Enzymol 579:103–24
    [Google Scholar]
  33. 33. 
    Zivanov J, Nakane T, Scheres SHW 2019. A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis. IUCrJ 6:15–17
    [Google Scholar]
  34. 34. 
    Scheres SHW. 2012. RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180:519–30
    [Google Scholar]
  35. 35. 
    Zivanov J, Nakane T, Forsberg BO, Kimanius D, Hagen WJ et al. 2018. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7:e42166
    [Google Scholar]
  36. 36. 
    Grant T, Rohou A, Grigorieff N 2018. cisTEM, user-friendly software for single-particle image processing. eLife 7:e35383
    [Google Scholar]
  37. 37. 
    Grigorieff N. 2016. Frealign: an exploratory tool for single-particle cryo-EM. Methods Enzymol 579:191–226
    [Google Scholar]
  38. 38. 
    Russo CJ, Henderson R. 2018. Ewald sphere correction using a single side-band image processing algorithm. Ultramicroscopy 187:26–33
    [Google Scholar]
  39. 39. 
    Glaeser RM, Typke D, Tiemeijer PC, Pulokas J, Cheng A 2011. Precise beam-tilt alignment and collimation are required to minimize the phase error associated with coma in high-resolution cryo-EM. J. Struct. Biol. 174:1–10
    [Google Scholar]
  40. 40. 
    McMullan G, Faruqi AR, Henderson R 2016. Direct electron detectors. Methods Enzymol 579:1–17
    [Google Scholar]
  41. 41. 
    Bai XC, McMullan G, Scheres SHW 2015. How cryo-EM is revolutionizing structural biology. Trends Biochem. Sci. 40:49–57
    [Google Scholar]
  42. 42. 
    Taylor KA, Glaeser RM. 2008. Retrospective on the early development of cryoelectron microscopy of macromolecules and a prospective on opportunities for the future. J. Struct. Biol. 163:214–23
    [Google Scholar]
  43. 43. 
    Glaeser RM, Han BG. 2017. Opinion: hazards faced by macromolecules when confined to thin aqueous films. Biophys. Rep. 3:1–7
    [Google Scholar]
  44. 44. 
    Noble AJ, Wei H, Dandey VP, Zhang Z, Tan YZ et al. 2018. Reducing effects of particle adsorption to the air-water interface in cryo-EM. Nat. Methods 15:793–95
    [Google Scholar]
  45. 45. 
    Masiulis S, Desai R, Uchanski T, Serna Martin I, Laverty D et al. 2019. GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565:454–59
    [Google Scholar]
  46. 46. 
    Laverty D, Desai R, Uchanski T, Masiulis S, Stec WJ et al. 2019. Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer. Nature 565:516–20
    [Google Scholar]
  47. 47. 
    Russo CJ, Passmore LA. 2016. Progress towards an optimal specimen support for electron cryomicroscopy. Curr. Opin. Struct. Biol. 37:81–89
    [Google Scholar]
  48. 48. 
    Danev R, Buijsse B, Khoshouei M, Plitzko JM, Baumeister W 2014. Volta potential phase plate for in-focus phase contrast transmission electron microscopy. PNAS 111:15635–40
    [Google Scholar]
  49. 49. 
    Khoshouei M, Radjainia M, Baumeister W, Danev R 2017. Cryo-EM structure of haemoglobin at 3.2 Å determined with the Volta phase plate. Nat. Commun. 8:16099
    [Google Scholar]
  50. 50. 
    Danev R, Tegunov D, Baumeister W 2017. Using the Volta phase plate with defocus for cryo-EM single particle analysis. eLife 6:e23006
    [Google Scholar]
  51. 51. 
    Danev R, Baumeister W. 2016. Cryo-EM single particle analysis with the Volta phase plate. eLife 5:e13046
    [Google Scholar]
  52. 52. 
    von Loeffelholz O, Papai G, Danev R, Myasnikov AG, Natchiar SK et al. 2018. Volta phase plate data collection facilitates image processing and cryo-EM structure determination. J. Struct. Biol. 202:191–99
    [Google Scholar]
  53. 53. 
    García-Nafría J, Lee Y, Bai X, Carpenter B, Tate CG 2018. Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. eLife 7:e35946
    [Google Scholar]
  54. 54. 
    García-Nafría J, Nehme R, Edwards PC, Tate CG 2018. Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature 558:620–23
    [Google Scholar]
  55. 55. 
    Draper-Joyce CJ, Khoshouei M, Thal DM, Liang YL, Nguyen ATN et al. 2018. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 558:559–63
    [Google Scholar]
  56. 56. 
    Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P et al. 2018. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555:121–25
    [Google Scholar]
  57. 57. 
    Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A et al. 2017. Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature 546:118–23
    [Google Scholar]
  58. 58. 
    Liang YL, Khoshouei M, Deganutti G, Glukhova A, Koole C et al. 2018. Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561:492–97
    [Google Scholar]
  59. 59. 
    Herzik MA Jr., Wu M, Lander GC. 2019. High-resolution structure determination of sub-100 kDa complexes using conventional cryo-EM. Nat. Commun. 10:1032
    [Google Scholar]
  60. 60. 
    Strege A, Carpenter B, Edwards PC, Tate CG 2017. Strategy for the thermostabilization of an agonist-bound GPCR coupled to a G protein. Methods Enzymol 594:243–64
    [Google Scholar]
  61. 61. 
    Magnani F, Serrano-Vega MJ, Shibata Y, Abdul-Hussein S, Lebon G et al. 2016. A mutagenesis and screening strategy to generate optimally thermostabilized membrane proteins for structural studies. Nat. Protoc. 11:1554–71
    [Google Scholar]
  62. 62. 
    Robertson N, Jazayeri A, Errey J, Baig A, Hurrell E et al. 2011. The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Neuropharmacology 60:36–44
    [Google Scholar]
  63. 63. 
    Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P et al. 2016. Breaking cryo-EM resolution barriers to facilitate drug discovery. Cell 165:1698–707
    [Google Scholar]
  64. 64. 
    Li H, O'Donoghue AJ, van der Linden WA, Xie SC, Yoo E et al. 2016. Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530:233–36
    [Google Scholar]
  65. 65. 
    Morris EP, da Fonseca PCA 2017. High-resolution cryo-EM proteasome structures in drug development. Acta Crystallogr. D Struct. Biol. 73:522–33
    [Google Scholar]
  66. 66. 
    Liao M, Cao E, Julius D, Cheng Y 2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107–12
    [Google Scholar]
  67. 67. 
    Gao Y, Cao E, Julius D, Cheng Y 2016. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534:347–51
    [Google Scholar]
  68. 68. 
    Congreve M, Oswald C, Marshall FH 2017. Applying structure-based drug design approaches to allosteric modulators of GPCRs. Trends Pharmacol. Sci. 38:837–47
    [Google Scholar]
  69. 69. 
    Congreve M, Dias JM, Marshall FH 2014. Structure-based drug design for G protein-coupled receptors. Prog. Med. Chem. 53:1–63
    [Google Scholar]
  70. 70. 
    Rucktooa P, Cheng RKY, Segala E, Geng T, Errey JC et al. 2018. Towards high throughput GPCR crystallography: in meso soaking of adenosine A2A receptor crystals. Sci. Rep. 8:41
    [Google Scholar]
  71. 71. 
    Collins PM, Douangamath A, Talon R, Dias A, Brandao-Neto J et al. 2018. Achieving a good crystal system for crystallographic X-ray fragment screening. Methods Enzymol 610:251–64
    [Google Scholar]
  72. 72. 
    Kimanius D, Forsberg BO, Scheres SH, Lindahl E 2016. Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2. eLife 5:e18722
    [Google Scholar]
  73. 73. 
    Heymann JB. 2018. Map challenge assessment: fair comparison of single particle cryoEM reconstructions. J. Struct. Biol. 204:360–67
    [Google Scholar]
  74. 74. 
    Gomez-Blanco J, de la Rosa-Trevin JM, Marabini R, Del Cano L, Jimenez A et al. 2018. Using Scipion for stream image processing at Cryo-EM facilities. J. Struct. Biol. 204:457–63
    [Google Scholar]
  75. 75. 
    Terwilliger TC, Adams PD, Afonine PV, Sobolev OV 2018. A fully automatic method yielding initial models from high-resolution cryo-electron microscopy maps. Nat. Methods 15:905–8
    [Google Scholar]
  76. 76. 
    Mendez JH, Stagg SM. 2018. Assessing the quality of single particle reconstructions by atomic model building. J. Struct. Biol. 204:276–82
    [Google Scholar]
  77. 77. 
    Sieghart W. 1995. Structure and pharmacology of γ-aminobutyric acidA receptor subtypes. Pharmacol. Rev. 47:181–234
    [Google Scholar]
  78. 78. 
    Sigel E, Steinmann ME. 2012. Structure, function, and modulation of GABAA receptors. J. Biol. Chem. 287:40224–31
    [Google Scholar]
  79. 79. 
    Farrant M, Nusser Z. 2005. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6:215–29
    [Google Scholar]
  80. 80. 
    Rudolph U, Mohler H. 2014. GABAA receptor subtypes: therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu. Rev. Pharmacol. Toxicol. 54:483–507
    [Google Scholar]
  81. 81. 
    Belelli D, Lambert JJ. 2005. Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 6:565–75
    [Google Scholar]
  82. 82. 
    Hosie AM, Wilkins ME, da Silva HM, Smart TG 2006. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444:486–89
    [Google Scholar]
  83. 83. 
    Chua HC, Chebib M. 2017. GABAA receptors and the diversity in their structure and pharmacology. Adv. Pharmacol. 79:1–34
    [Google Scholar]
  84. 84. 
    Braat S, Kooy RF. 2015. The GABAA receptor as a therapeutic target for neurodevelopmental disorders. Neuron 86:1119–30
    [Google Scholar]
  85. 85. 
    Franks NP. 2008. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat. Rev. Neurosci. 9:370–86
    [Google Scholar]
  86. 86. 
    Rudolph U, Knoflach F. 2011. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat. Rev. Drug Discov. 10:685–97
    [Google Scholar]
  87. 87. 
    Thompson SA, Whiting PJ, Wafford KA 1996. Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination. Br. J. Pharmacol. 117:521–27
    [Google Scholar]
  88. 88. 
    Wallner M, Hanchar HJ, Olsen RW 2003. Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans. PNAS 100:15218–23
    [Google Scholar]
  89. 89. 
    Simon J, Wakimoto H, Fujita N, Lalande M, Barnard EA 2004. Analysis of the set of GABAA receptor genes in the human genome. J. Biol. Chem. 279:41422–35
    [Google Scholar]
  90. 90. 
    Olsen RW, Sieghart W. 2008. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol. Rev. 60:243–60
    [Google Scholar]
  91. 91. 
    Knoflach F, Benke D, Wang Y, Scheurer L, Luddens H et al. 1996. Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2. Mol. Pharmacol. 50:1253–61
    [Google Scholar]
  92. 92. 
    Tan KR, Rudolph U, Luscher C 2011. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 34:188–97
    [Google Scholar]
  93. 93. 
    Miller PS, Smart TG. 2010. Binding, activation and modulation of Cys-loop receptors. Trends Pharmacol. Sci. 31:161–74
    [Google Scholar]
  94. 94. 
    Miller PS, Aricescu AR. 2014. Crystal structure of a human GABAA receptor. Nature 512:270–75
    [Google Scholar]
  95. 95. 
    Laverty D, Thomas P, Field M, Andersen OJ, Gold MG et al. 2017. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat. Struct. Mol. Biol. 24:977–85
    [Google Scholar]
  96. 96. 
    Chen Q, Wells MM, Arjunan P, Tillman TS, Cohen AE et al. 2018. Structural basis of neurosteroid anesthetic action on GABAA receptors. Nat. Commun. 9:3972
    [Google Scholar]
  97. 97. 
    Miller PS, Scott S, Masiulis S, De Colibus L, Pardon E et al. 2017. Structural basis for GABAA receptor potentiation by neurosteroids. Nat. Struct. Mol. Biol. 24:986–92
    [Google Scholar]
  98. 98. 
    Liu S, Xu L, Guan F, Liu YT, Cui Y et al. 2018. Cryo-EM structure of the human α5β3 GABAA receptor. Cell Res 28:958–61
    [Google Scholar]
  99. 99. 
    Phulera S, Zhu H, Yu J, Claxton DP, Yoder N et al. 2018. Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA. eLife 7:e39383
    [Google Scholar]
  100. 100. 
    Zhu S, Noviello CM, Teng J, Walsh RM Jr., Kim JJ, Hibbs RE 2018. Structure of a human synaptic GABAA receptor. Nature 559:67–72
    [Google Scholar]
  101. 101. 
    Walters RJ, Hadley SH, Morris KD, Amin J 2000. Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Nat. Neurosci. 3:1274–81
    [Google Scholar]
  102. 102. 
    Kobilka BK, Deupi X. 2007. Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 28:397–406
    [Google Scholar]
  103. 103. 
    Pierce KL, Premont RT, Lefkowitz RJ 2002. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3:639–50
    [Google Scholar]
  104. 104. 
    Oldham WM, Hamm HE. 2008. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 9:60–71
    [Google Scholar]
  105. 105. 
    Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS et al. 2017. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16:19–34
    [Google Scholar]
  106. 106. 
    Carpenter B, Nehme R, Warne T, Leslie AG, Tate CG 2016. Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 536:104–7
    [Google Scholar]
  107. 107. 
    Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY et al. 2011. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477:549–55
    [Google Scholar]
  108. 108. 
    Tsai CJ, Pamula F, Nehme R, Muhle J, Weinert T et al. 2018. Crystal structure of rhodopsin in complex with a mini-Go sheds light on the principles of G protein selectivity. Sci. Adv. 4:eaat7052
    [Google Scholar]
  109. 109. 
    Ghosh E, Kumari P, Jaiman D, Shukla AK 2015. Methodological advances: the unsung heroes of the GPCR structural revolution. Nat. Rev. Mol. Cell Biol. 16:69–81
    [Google Scholar]
  110. 110. 
    Chun E, Thompson AA, Liu W, Roth CB, Griffith MT et al. 2012. Fusion partner toolchest for the stabilization and crystallization of G protein–coupled receptors. Structure 20:967–76
    [Google Scholar]
  111. 111. 
    Cho KH, Husri M, Amin A, Gotfryd K, Lee HJ et al. 2015. Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study. Analyst 140:3157–63
    [Google Scholar]
  112. 112. 
    Aherne M, Lyons JA, Caffrey M 2012. A fast, simple and robust protocol for growing crystals in the lipidic cubic phase. J. Appl. Crystallogr. 45:1330–33
    [Google Scholar]
  113. 113. 
    Warren AJ, Axford D, Paterson NG, Owen RL 2016. Exploiting microbeams for membrane protein structure determination. Adv. Exp. Med. Biol. 922:105–17
    [Google Scholar]
  114. 114. 
    Zhang X, Stevens RC, Xu F 2015. The importance of ligands for G protein–coupled receptor stability. Trends Biochem. Sci. 40:79–87
    [Google Scholar]
  115. 115. 
    Lebon G, Warne T, Tate CG 2012. Agonist-bound structures of G protein–coupled receptors. Curr. Opin. Struct. Biol. 22:482–90
    [Google Scholar]
  116. 116. 
    Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N et al. 2008. Crystal structure of opsin in its G-protein-interacting conformation. Nature 455:497–502
    [Google Scholar]
  117. 117. 
    Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P et al. 2011. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469:175–80
    [Google Scholar]
  118. 118. 
    dal Maso E, Glukhova A, Zhu Y, Garcia-Nafria J, Tate CG, Atanasio S et al. 2019. The molecular control of calcitonin receptor signaling. ACS Pharmacol. Trans. Sci. 2:31–51
    [Google Scholar]
  119. 119. 
    Zhang Y, Sun B, Feng D, Hu H, Chu M et al. 2017. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248–53
    [Google Scholar]
  120. 120. 
    Kang Y, Kuybeda O, de Waal PW, Mukherjee S, Van Eps N et al. 2018. Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature 558:553–58
    [Google Scholar]
  121. 121. 
    Koehl A, Hu H, Maeda S, Zhang Y, Qu Q et al. 2018. Structure of the μ-opioid receptor-Gi protein complex. Nature 558:547–52
    [Google Scholar]
  122. 122. 
    Krishna Kumar K, Shalev-Benami M, Robertson MJ, Hu H, Banister SD et al. 2019. Structure of a signaling cannabinoid receptor 1-G protein complex. Cell 176:448–58.e12
    [Google Scholar]
  123. 123. 
    McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J et al. 1998. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–39
    [Google Scholar]
  124. 124. 
    Koehl A, Hu H, Feng D, Sun B, Zhang Y et al. 2019. Structural insights into the activation of metabotropic glutamate receptors. Nature 566:79–84
    [Google Scholar]
  125. 125. 
    Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K et al. 2014. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511:557–62
    [Google Scholar]
  126. 126. 
    Wu H, Wang C, Gregory KJ, Han GW, Cho HP et al. 2014. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344:58–64
    [Google Scholar]
  127. 127. 
    Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M et al. 2000. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407:971–77
    [Google Scholar]
  128. 128. 
    Shaik MM, Peng H, Lu J, Rits-Volloch S, Xu C et al. 2019. Structural basis of coreceptor recognition by HIV-1 envelope spike. Nature 565:318–23
    [Google Scholar]
  129. 129. 
    Kotev M, Pascual R, Almansa C, Guallar V, Soliva R 2018. Pushing the limits of computational structure-based drug design with a cryo-EM structure: the Ca2+ channel α2δ-1 subunit as a test case. J. Chem. Inf. Model. 58:1707–15
    [Google Scholar]
  130. 130. 
    Muller H, Jin J, Danev R, Spence J, Padmore H, Glaeser RM 2010. Design of an electron microscope phase plate using a focused continuous-wave laser. New J. Phys. 12:073011
    [Google Scholar]
  131. 131. 
    Dandey VP, Wei H, Zhang Z, Tan YZ, Acharya P et al. 2018. Spotiton: new features and applications. J. Struct. Biol. 202:161–69
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010919-023545
Loading
/content/journals/10.1146/annurev-pharmtox-010919-023545
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