EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Asymmetric activation of the calcium-sensing receptor homodimer.
ジャーナル・号・ページ	Nature, Vol. 595, Issue 7867, Page 455-459, Year 2021
掲載日	2021年6月30日
著者	Yang Gao / Michael J Robertson / Sabrina N Rahman / Alpay B Seven / Chensong Zhang / Justin G Meyerowitz / Ouliana Panova / Fadil M Hannan / Rajesh V Thakker / Hans Bräuner-Osborne / Jesper M Mathiesen / Georgios Skiniotis /
PubMed 要旨	The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid ...The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.
リンク	Nature / PubMed:34194040 / PubMed Central
手法	EM (単粒子)
解像度	2.5 - 4.1 Å
構造データ	23652 7m3e EMDB-23652, PDB-7m3e: Asymmetric Activation of the Calcium Sensing Receptor Homodimer 手法: EM (単粒子) / 解像度: 3.2 Å 23653 7m3f EMDB-23653, PDB-7m3f: Asymmetric Activation of the Calcium Sensing Receptor Homodimer 手法: EM (単粒子) / 解像度: 2.8 Å 23654 7m3g EMDB-23654, PDB-7m3g: Asymmetric Activation of the Calcium Sensing Receptor Homodimer 手法: EM (単粒子) / 解像度: 2.5 Å 23655 7m3j EMDB-23655, PDB-7m3j: Asymmetric Activation of the Calcium Sensing Receptor Homodimer 手法: EM (単粒子) / 解像度: 4.1 Å
化合物	ChemComp-YP1: 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile / 2-[(R)-2-ヒドロキシ-3-[1,1-ジメチル-2-(2-ナフチル)エチルアミノ]プロポキシ]-6-クロロベンゾ(以下略) / アンタゴニスト, ホルモンYM / NPS-2143 ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン ChemComp-TRP: TRYPTOPHAN / トリプトファン / トリプトファン ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-PO4: PHOSPHATE ION / ホスファ-ト / リン酸塩 ChemComp-YP4: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine / シナカルセト / 薬剤YM / シナカルセト ChemComp-H43: 2-[4-[(3S)-3-[[(1R)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]ethanoic acid / アゴニスト*YM / Evocalcet
由来	homo sapiens (ヒト) synthetic construct (人工物)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / GPCR (Gタンパク質共役受容体) / calcium sensing receptor (カルシウム感知受容体) / negative allosteric modulator / family C GPCR / active state / positive allosteric modulator (アロステリック調節因子)