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-Structure paper
タイトル | Symmetric activation and modulation of the human calcium-sensing receptor. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 118, Issue 51, Year 2021 |
掲載日 | 2021年12月21日 |
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 / |
PubMed 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. |
リンク | Proc Natl Acad Sci U S A / PubMed:34916296 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.7 - 5.9 Å |
構造データ | EMDB-25143, PDB-7sil: EMDB-25144, PDB-7sim: EMDB-25145, PDB-7sin: |
化合物 | ChemComp-NAG: ChemComp-TCR: ChemComp-PO4: ChemComp-CA: ChemComp-9IG: ChemComp-CLR: ChemComp-YP1: |
由来 |
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キーワード | MEMBRANE PROTEIN / calcium-sensing receptor / cryo-EM structure / allosteric modulation / activation mechanism / symmetry |