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Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.

<div class='caption-title'>Effects of G protein association and cellular cholesterol on CCK-8 binding and biological activity.</div>
<div class='caption-title'>Cryo-EM structure of CCK-8/CCK1R in complex with DNGαs/Gβ1γ2/Nb35 or mGαsqi/Gβ1γ2/scFv16.</div>
<div class='caption-title'>G protein interactions with activated CCK1R.</div>
Mobbs JI, Belousoff MJ, Harikumar KG, Piper SJ, Xu X, Furness SGB, Venugopal H, Christopoulos A, Danev R, Wootten D, Thal DM, Miller LJ, Sexton PM
OpenAccess logo PLoS Biol 19 e3001295 (2021)
Cited: 39 times
EuropePMC logo PMID: 34086670

Abstract

G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-α5 helix (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from "unwinding" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.

Reviews - 7mby mentioned but not cited (1)

  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

Articles - 7mby mentioned but not cited (9)

  1. Structures of neurokinin 1 receptor in complex with Gq and Gs proteins reveal substance P binding mode and unique activation features. Thom C, Ehrenmann J, Vacca S, Waltenspühl Y, Schöppe J, Medalia O, Plückthun A. Sci Adv 7 eabk2872 (2021)
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  6. Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling. Harikumar KG, Zhao P, Cary BP, Xu X, Desai AJ, Dong M, Mobbs JI, Toufaily C, Furness SGB, Christopoulos A, Belousoff MJ, Wootten D, Sexton PM, Miller LJ. PLoS Biol 22 e3002673 (2024)
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Reviews citing this publication (5)

  1. Structure determination of GPCRs: cryo-EM compared with X-ray crystallography. García-Nafría J, Tate CG. Biochem Soc Trans 49 2345-2355 (2021)
  2. New insights into GPCR coupling and dimerisation from cryo-EM structures. Gusach A, García-Nafría J, Tate CG. Curr Opin Struct Biol 80 102574 (2023)
  3. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  4. Structure, function and drug discovery of GPCR signaling. Cheng L, Xia F, Li Z, Shen C, Yang Z, Hou H, Sun S, Feng Y, Yong X, Tian X, Qin H, Yan W, Shao Z. Mol Biomed 4 46 (2023)
  5. Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues. Navarro-Lérida I, Aragay AM, Asensio A, Ribas C. Antioxidants (Basel) 11 1599 (2022)

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  3. Routine sub-2.5 Å cryo-EM structure determination of GPCRs. Danev R, Belousoff M, Liang YL, Zhang X, Eisenstein F, Wootten D, Sexton PM. Nat Commun 12 4333 (2021)
  4. Molecular insights into the regulation of constitutive activity by RNA editing of 5HT2C serotonin receptors. Gumpper RH, Fay JF, Roth BL. Cell Rep 40 111211 (2022)
  5. Structural basis of neuropeptide Y signaling through Y1 receptor. Park C, Kim J, Ko SB, Choi YK, Jeong H, Woo H, Kang H, Bang I, Kim SA, Yoon TY, Seok C, Im W, Choi HJ. Nat Commun 13 853 (2022)
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  7. New Insights into the Structure and Function of Class B1 GPCRs. Cary BP, Zhang X, Cao J, Johnson RM, Piper SJ, Gerrard EJ, Wootten D, Sexton PM. Endocr Rev 44 492-517 (2023)
  8. Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics. Vuckovic Z, Wang J, Pham V, Mobbs JI, Belousoff MJ, Bhattarai A, Burger WAC, Thompson G, Yeasmin M, Nawaratne V, Leach K, van der Westhuizen ET, Khajehali E, Liang YL, Glukhova A, Wootten D, Lindsley CW, Tobin A, Sexton P, Danev R, Valant C, Miao Y, Christopoulos A, Thal DM. Elife 12 e83477 (2023)
  9. Effect of Ligands and Transducers on the Neurotensin Receptor 1 Conformational Ensemble. Dixon AD, Inoue A, Robson SA, Culhane KJ, Trinidad JC, Sivaramakrishnan S, Bumbak F, Ziarek JJ. J Am Chem Soc 144 10241-10250 (2022)
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  12. Processing of a plant peptide hormone precursor facilitated by posttranslational tyrosine sulfation. Royek S, Bayer M, Pfannstiel J, Pleiss J, Ingram G, Stintzi A, Schaller A. Proc Natl Acad Sci U S A 119 e2201195119 (2022)
  13. Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol. Harikumar KG, Coudrat T, Desai AJ, Dong M, Dengler DG, Furness SGB, Christopoulos A, Wootten D, Sergienko EA, Sexton PM, Miller LJ. Front Endocrinol (Lausanne) 12 789957 (2021)
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  15. Molecular mechanism of the wake-promoting agent TAK-925. Yin J, Kang Y, McGrath AP, Chapman K, Sjodt M, Kimura E, Okabe A, Koike T, Miyanohana Y, Shimizu Y, Rallabandi R, Lian P, Bai X, Flinspach M, De Brabander JK, Rosenbaum DM. Nat Commun 13 2902 (2022)
  16. Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling. Nie Y, Qiu Z, Chen S, Chen Z, Song X, Ma Y, Huang N, Cyster JG, Zheng S. Nat Commun 14 5901 (2023)
  17. Mechanism of Action and Structure-Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor. Dengler DG, Harikumar KG, Yen A, Sergienko EA, Miller LJ. Membranes (Basel) 13 150 (2023)
  18. Letter Molecular basis for the activation of thyrotropin-releasing hormone receptor. Ji SY, Dong YJ, Chen LN, Zang SK, Wang J, Shen DD, Guo J, Qin J, Zhang H, Wang WW, Shen Q, Zhang Y, Song Z, Mao C. Cell Discov 8 116 (2022)
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  20. Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling. Mukhaleva E, Ma N, van der Velden WJC, Gogoshin G, Branciamore S, Bhattacharya S, Rodin AS, Vaidehi N. J Biol Chem 300 107362 (2024)
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Related citations provided by authors (1)

  1. Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity. Mobbs J, Belousoff MJ, Harikumar KG, Piper SJ, Xu X, Furness SGB, Venugopal H, Christopoulos A, Danev R, Wootten D, Thal DM, Miller LJ, Sexton PM Biorxiv - (2021)

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