Journal
SCIENCE ADVANCES
Volume 7, Issue 23, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg1483
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Funding
- National Key Research and Development Program of China [2018YFA0507700]
- National Natural Science Foundation of China [91954119, 31870736, 31870834, 32071231]
- Fundamental Research Funds for the Central Universities [035-63201109]
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CaSR is a crucial receptor for calcium homeostasis and hormone secretion. Study of its structures in different ligand-bound states provides insights into activation mechanism, allosteric modulation, and disease therapy. The negative allosteric modulator NPS-2143 induces structural rearrangement leading to an inactivated interface.
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.
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