Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor
Tianlei Wen, Ziyu Wang, Xiaozhe Chen, Yue Ren, Xuhang Lu, Yangfei Xing, Jing Lu, Shenghai Chang, Xing Zhang, Yuequan Shen, Xue Yang
Abstract
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.