7dd6

Publication Abstract from PubMed

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 (Ca(2+) 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.

Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.,Wen T, Wang Z, Chen X, Ren Y, Lu X, Xing Y, Lu J, Chang S, Zhang X, Shen Y, Yang X Sci Adv. 2021 Jun 4;7(23). pii: 7/23/eabg1483. doi: 10.1126/sciadv.abg1483. Print, 2021 Jun. PMID:34088669^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.