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Data from: Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

Cite this dataset

Wen, Tianlei et al. (2024). Data from: Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor [Dataset]. Dryad. https://doi.org/10.5061/dryad.pk0p2ngxj

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.

README: Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

https://doi.org/10.5061/dryad.pk0p2ngxj

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.

Sharing/Access information

Atomic coordinates have been deposited in the Protein Data Bank under accession number 7DD6 (7dd6.pdb) for ggCaSR-active, 7DD5 for ggCaSR-NAM, and 7DD7 for ggCaSR-PAM. The cryo-EM density maps have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-30646, EMD-30645, EMD-30644, and EMD-30647 for ggCaSR-inactive, ggCaSR-active, ggCaSR-NAM, and ggCaSR-PAM, respectively.

Funding

National Natural Science Foundation of China, Award: 32271288

National Natural Science Foundation of China, Award: 32071231

Haihe Laboratory of Synthetic Biology, Award: 22HHSWSS00009, Innovation Talent Program

National Natural Science Foundation of China, Award: 91954119

National Natural Science Foundation of China, Award: 31870736

National Natural Science Foundation of China, Award: 31870834

Fundamental Research Funds for the Central Universities, Award: 035-63201110

Fundamental Research Funds for the Central Universities, Award: 035-63201109

Chinese Ministry of Science and Technology, Award: 2017YFA0504800, National Key Research and Development Program of China

Chinese Ministry of Science and Technology, Award: 2017YFA0504800, National Key Research and Development Program of China

Chinese Ministry of Science and Technology, Award: 2018YFA0507700, National Key Research and Development Program of China