National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM141871
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM29169
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
P41GM116799
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM107462
米国
Simons Foundation
SF349247
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103310
米国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2021 タイトル: Symmetric activation and modulation of the human calcium-sensing receptor. 著者: Jinseo Park / Hao Zuo / Aurel Frangaj / Ziao Fu / Laura Y Yen / Zhening Zhang / Lidia Mosyak / Vesna N Slavkovich / Jonathan Liu / Kimberly M Ray / Baohua Cao / Francesca Vallese / Yong Geng ...著者: Jinseo Park / Hao Zuo / Aurel Frangaj / Ziao Fu / Laura Y Yen / Zhening Zhang / Lidia Mosyak / Vesna N Slavkovich / Jonathan Liu / Kimberly M Ray / Baohua Cao / Francesca Vallese / Yong Geng / Shaoxia Chen / Robert Grassucci / Venkata P Dandey / Yong Zi Tan / Edward Eng / Yeji Lee / Brian Kloss / Zheng Liu / Wayne A Hendrickson / Clinton S Potter / Bridget Carragher / Joseph Graziano / Arthur D Conigrave / Joachim Frank / Oliver B Clarke / Qing R Fan / 要旨: The human extracellular calcium-sensing (CaS) receptor controls plasma Ca levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS ...The human extracellular calcium-sensing (CaS) receptor controls plasma Ca levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.
EMPIAR-10835 (タイトル: Structure of negative allosteric modulator-bound inactive human calcium-sensing receptor Data size: 4.0 TB Data #1: Unaligned multi-frame micrographs of calcium-sensing receptor in NAM-bound inactive state [micrographs - multiframe])