7DD5

Structure of Calcium-Sensing Receptor in complex with NPS-2143

Summary for 7DD5

• Entry DOI: 10.2210/pdb7dd5/pdb
• EMDB information: 30644
• Descriptor: Calcium-Sensing Receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CHLORIDE ION, ... (8 entities in total)
• Functional Keywords: calcium-sensing receptor, casr, nps-2143, membrane protein
• Biological source: Gallus gallus
• Total number of polymer chains: 2
• Total formula weight: 243190.99

Authors

Wen, T.L.,Yang, X.,Shen, Y.Q. (deposition date: 2020-10-27, release date: 2021-06-16, Last modification date: 2024-10-16)

Primary citation

Wen, T.,Wang, Z.,Chen, X.,Ren, Y.,Lu, X.,Xing, Y.,Lu, J.,Chang, S.,Zhang, X.,Shen, Y.,Yang, X.
Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.
Sci Adv, 7:-, 2021

PubMed 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 (Ca 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.

PubMed: 34088669
DOI: 10.1126/sciadv.abg1483

Experimental method

ELECTRON MICROSCOPY (3.2 Å)