8SZI

Cryo-EM structure of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs

8SZI の概要

• エントリーDOI: 10.2210/pdb8szi/pdb
• EMDBエントリー: 40917
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-3, TRYPTOPHAN, PHOSPHATE ION, ... (12 entities in total)
• 機能のキーワード: family c gpcr, calcium-sensing receptor (casr), heterotrimeric g protein, cryo-em, lipid nanodiscs, positive allosteric modulator, membrane protein, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 304841.78

構造登録者

He, F.,Wu, C.,Gao, Y.,Skiniotis, G. (登録日: 2023-05-29, 公開日: 2024-02-07, 最終更新日: 2024-11-13)

主引用文献

He, F.,Wu, C.G.,Gao, Y.,Rahman, S.N.,Zaoralova, M.,Papasergi-Scott, M.M.,Gu, T.J.,Robertson, M.J.,Seven, A.B.,Li, L.,Mathiesen, J.M.,Skiniotis, G.
Allosteric modulation and G-protein selectivity of the Ca 2+ -sensing receptor.
Nature, 626:1141-1148, 2024

PubMed Abstract: The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G versus G proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G and G drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G and G coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.

PubMed: 38326620
DOI: 10.1038/s41586-024-07055-2

実験手法

ELECTRON MICROSCOPY (3.5 Å)