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Asymmetric activation of the calcium-sensing receptor homodimer.

Gao Y, Robertson MJ, Rahman SN, Seven AB, Zhang C, Meyerowitz JG, Panova O, Hannan FM, Thakker RV, Bräuner-Osborne H, Mathiesen JM, Skiniotis G
Nature 595 455-459 (2021)
Related entries: 7m3f, 7m3g, 7m3j

Cited: 45 times
EuropePMC logo PMID: 34194040

Abstract

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders1. CaSR is a family C G-protein-coupled receptor2 that functions as an obligate homodimer, with each protomer composed of a Ca2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.

Reviews - 7m3e mentioned but not cited (2)

  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)
  2. G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery. Zhang M, Chen T, Lu X, Lan X, Chen Z, Lu S. Signal Transduct Target Ther 9 88 (2024)

Articles - 7m3e mentioned but not cited (4)

  1. Asymmetric activation of the calcium-sensing receptor homodimer. Gao Y, Robertson MJ, Rahman SN, Seven AB, Zhang C, Meyerowitz JG, Panova O, Hannan FM, Thakker RV, Bräuner-Osborne H, Mathiesen JM, Skiniotis G. Nature 595 455-459 (2021)
  2. Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning. Schamber MR, Vafabakhsh R. Nat Commun 13 2194 (2022)
  3. Case Reports Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications. Elston MS, Elajnaf T, Hannan FM, Thakker RV. J Endocr Soc 6 bvac042 (2022)
  4. research-article Small vs. Large Library Docking for Positive Allosteric Modulators of the Calcium Sensing Receptor. Liu F, Wu CG, Tu CL, Glenn I, Meyerowitz J, Levit Kaplan A, Lyu J, Cheng Z, Tarkhanova OO, Moroz YS, Irwin JJ, Chang W, Shoichet BK, Skiniotis G. bioRxiv 2023.12.27.573448 (2024)


Reviews citing this publication (8)

  1. Allosteric modulation of G protein-coupled receptor signaling. Shen S, Zhao C, Wu C, Sun S, Li Z, Yan W, Shao Z. Front Endocrinol (Lausanne) 14 1137604 (2023)
  2. Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives. Goralski T, Ram JL. Int J Mol Sci 23 717 (2022)
  3. 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)
  4. Calcium-Sensing Receptor (CaSR)-Mediated Intracellular Communication in Cardiovascular Diseases. Chu H, Qin Z, Ma J, Xie Y, Shi H, Gu J, Shi B. Cells 11 3075 (2022)
  5. Class A and C GPCR Dimers in Neurodegenerative Diseases. Caniceiro AB, Bueschbell B, Schiedel AC, Moreira IS. Curr Neuropharmacol 20 2081-2141 (2022)
  6. Inhibition of the calcium-sensing receptor by extracellular phosphate ions and by intracellular phosphorylation. Centeno PP, Binmahfouz LS, Alghamdi K, Ward DT. Front Physiol 14 1154374 (2023)
  7. Exploring GPCR conformational dynamics using single-molecule fluorescence. Agyemang E, Gonneville AN, Tiruvadi-Krishnan S, Lamichhane R. Methods 226 35-48 (2024)
  8. Molecular regulation of calcium-sensing receptor (CaSR)-mediated signaling. Tian L, Andrews C, Yan Q, Yang JJ. Chronic Dis Transl Med 10 167-194 (2024)

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  1. G-protein activation by a metabotropic glutamate receptor. Seven AB, Barros-Álvarez X, de Lapeyrière M, Papasergi-Scott MM, Robertson MJ, Zhang C, Nwokonko RM, Gao Y, Meyerowitz JG, Rocher JP, Schelshorn D, Kobilka BK, Mathiesen JM, Skiniotis G. Nature 595 450-454 (2021)
  2. The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites. Hedderich JB, Persechino M, Becker K, Heydenreich FM, Gutermuth T, Bouvier M, Bünemann M, Kolb P. Nat Commun 13 2567 (2022)
  3. Symmetric activation and modulation of the human calcium-sensing receptor. Park J, Zuo H, Frangaj A, Fu Z, Yen LY, Zhang Z, Mosyak L, Slavkovich VN, Liu J, Ray KM, Cao B, Vallese F, Geng Y, Chen S, Grassucci R, Dandey VP, Tan YZ, Eng E, Lee Y, Kloss B, Liu Z, Hendrickson WA, Potter CS, Carragher B, Graziano J, Conigrave AD, Frank J, Clarke OB, Fan QR. Proc Natl Acad Sci U S A 118 e2115849118 (2021)
  4. Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface. Liu L, Fan Z, Rovira X, Xue L, Roux S, Brabet I, Xin M, Pin JP, Rondard P, Liu J. Elife 10 e70188 (2021)
  5. Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives. Ullah A, Khan J, Waheed A, Sharma N, Pryor EK, Stumpe TR, Velasquez Zarate L, Cason FD, Kumar S, Misra S, Kavuri S, Mesa H, Roper N, Foroutan S, Karki NR, Del Rivero J, Simonds WF, Karim NA. Cancers (Basel) 14 1426 (2022)
  6. Applications of Cryo-EM in small molecule and biologics drug design. Lees JA, Dias JM, Han S. Biochem Soc Trans 49 2627-2638 (2021)
  7. Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor. He F, Wu CG, Gao Y, Rahman SN, Zaoralová M, Papasergi-Scott MM, Gu TJ, Robertson MJ, Seven AB, Li L, Mathiesen JM, Skiniotis G. Nature 626 1141-1148 (2024)
  8. Structure of Mycobacterium tuberculosis Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases. Mehta V, Khanppnavar B, Schuster D, Kantarci I, Vercellino I, Kosturanova A, Iype T, Stefanic S, Picotti P, Korkhov VM. Elife 11 e77032 (2022)
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  10. Asymmetry is central to excitatory glutamate receptor activation. Gregory KJ. Nat Struct Mol Biol 28 633-635 (2021)
  11. Cell Surface Calcium-Sensing Receptor Heterodimers: Mutant Gene Dosage Affects Ca2+ Sensing but Not G Protein Interaction. Goolam MA, Brown AP, Edwards KT, Gregory KJ, Leach K, Conigrave AD. J Bone Miner Res 37 1787-1807 (2022)
  12. Functional Assessment of Calcium-Sensing Receptor Variants Confirms Familial Hypocalciuric Hypercalcemia. Mullin BH, Pavlos NJ, Brown SJ, Walsh JP, McKellar RA, Wilson SG, Ward BK. J Endocr Soc 6 bvac025 (2022)
  13. Constitutive activation mechanism of a class C GPCR. Shin J, Park J, Jeong J, Lam JH, Qiu X, Wu D, Kim K, Lee JY, Robinson CV, Hyun J, Katritch V, Kim KP, Cho Y. Nat Struct Mol Biol 31 678-687 (2024)
  14. Differential parathyroid and kidney Ca2+-sensing receptor activation in autosomal dominant hypocalcemia 1. van Megen WH, Tan RSG, Alexander RT, Dimke H. EBioMedicine 78 103947 (2022)
  15. Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3. Sanematsu K, Yamamoto M, Nagasato Y, Kawabata Y, Watanabe Y, Iwata S, Takai S, Toko K, Matsui T, Wada N, Shigemura N. Commun Biol 6 340 (2023)
  16. Letter Structural insights into asymmetric activation of the calcium-sensing receptor-Gq complex. Ling S, Meng X, Zhang Y, Xia Z, Zhou Y, Yang F, Shi P, Shi C, Tian C. Cell Res 34 169-172 (2024)
  17. Calcium-sensing receptor alleviates gut damage caused by endotoxemia by regulating gut microbiota. Sun Y, Song J, Liu H, Li L, Xiao K, Mao W, Jiang C. Transl Pediatr 12 2179-2190 (2023)
  18. Osteocalcin binds to a GPRC6A Venus fly trap allosteric site to positively modulate GPRC6A signaling. Agarwal R, Ye R, Smith MD, Smith JC, Quarles LD, Pi M. FASEB Bioadv 6 365-376 (2024)
  19. Radiofrequency Ablation of Parathyroid Glands to Treat a Patient With Hypercalcemia Caused by a Novel Inactivating Mutation in CaSR. Hao Y, Lei Z, Shi N, Yu L, Ji W, Zhang X. Front Endocrinol (Lausanne) 12 743517 (2021)
  20. Semisynthesis, Biological Evaluation and Molecular Docking Studies of Barbatic Acid Derivatives as Novel Diuretic Candidates. Yu X, Sui Y, Xi Y, Zhang Y, Luo G, Long Y, Yang W. Molecules 28 4010 (2023)
  21. Silicon-Rhodamine Functionalized Evocalcet Probes Potently and Selectively Label Calcium Sensing Receptors In Vitro, In Vivo, and Ex Vivo. Bátora D, Fischer JP, Kaderli RM, Varga M, Lochner M, Gertsch J. ACS Pharmacol Transl Sci 7 1557-1570 (2024)
  22. Absence of calcium-sensing receptor basal activity due to inter-subunit disulfide bridges. Ma S, Yin X, Pin JP, Rondard P, Yi P, Liu J. Commun Biol 7 501 (2024)
  23. Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains. Mancinelli CD, Marx DC, Gonzalez-Hernandez AJ, Huynh K, Mancinelli L, Arefin A, Khelashvilli G, Levitz J, Eliezer D. Proc Natl Acad Sci U S A 121 e2407744121 (2024)
  24. Cryo-EM structure of human class C orphan GPCR GPR179 involved in visual processing. Yun Y, Jeong H, Laboute T, Martemyanov KA, Lee HH. Nat Commun 15 8299 (2024)
  25. Direct binding of calmodulin to the cytosolic C-terminal regions of sweet/umami taste receptors. Yoshida A, Ito A, Yasui N, Yamashita A. J Biochem 174 451-459 (2023)
  26. Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer. Lin X, Provasi D, Niswender CM, Asher WB, Javitch JA. Nat Commun 15 8552 (2024)
  27. Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor. Matarage Don NNJ, Padmavathi R, Khasro TD, Zaman MRU, Ji HF, Ram JL, Ahn YH. ACS Chem Biol 19 1661-1670 (2024)
  28. Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders. Alhassen S, Hogenkamp D, Nguyen HA, Al Masri S, Abbott GW, Civelli O, Alachkar A. Brain 147 3379-3394 (2024)
  29. Promiscuous G-protein activation by the calcium-sensing receptor. Zuo H, Park J, Frangaj A, Ye J, Lu G, Manning JJ, Asher WB, Lu Z, Hu GB, Wang L, Mendez J, Eng E, Zhang Z, Lin X, Grassucci R, Hendrickson WA, Clarke OB, Javitch JA, Conigrave AD, Fan QR. Nature 629 481-488 (2024)
  30. Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization. Strauss A, Gonzalez-Hernandez AJ, Lee J, Abreu N, Selvakumar P, Salas-Estrada L, Kristt M, Arefin A, Huynh K, Marx DC, Gilliland K, Melancon BJ, Filizola M, Meyerson J, Levitz J. Nat Commun 15 6498 (2024)
  31. The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer. Yan P, Lin X, Wu L, Xu L, Li F, Liu J, Xu F. Nat Commun 15 5255 (2024)


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