EMD-30646
Structure of Calcium-Sensing Receptor in an inactive state
EMD-30646
Single-particle7.2 Å
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Map released: 16/06/2021
Last modified: 16/06/2021
Sample Organism:
Gallus gallus
Sample: Calcium-Sensing Receptor in an inactive state
Deposition Authors: Wen TL, Yang X, Shen YQ
Sample: Calcium-Sensing Receptor in an inactive state
Deposition Authors: Wen TL, Yang X, Shen YQ
Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.
Wen TL
,
Wang ZY,
Chen XZ,
Ren Y
,
Lu XH
,
Xing YF
,
Lu J
,
Chang SH
,
Zhang X
,
Shen YQ
,
Yang X
(2021) Sci Adv
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(2021) Sci Adv
Abstract:
Calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo-electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.
Calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo-electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.