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	Allosteric modulation and G-protein selectivity of the Ca-sensing receptor.
ジャーナル・号・ページ	Nature, Vol. 626, Issue 8001, Page 1141-1148, Year 2024
掲載日	2024年2月7日
著者	Feng He / Cheng-Guo Wu / Yang Gao / Sabrina N Rahman / Magda Zaoralová / Makaía M Papasergi-Scott / Ting-Jia Gu / Michael J Robertson / Alpay B Seven / Lingjun Li / Jesper M Mathiesen / Georgios Skiniotis /
PubMed 要旨	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 ...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.
リンク	Nature / PubMed:38326620
手法	EM (単粒子)
解像度	2.6 - 3.9 Å
構造データ	40914 8szf EMDB-40914, PDB-8szf: Cryo-EM structure of cinacalcet-bound active-state human calcium-sensing receptor CaSR in lipid nanodiscs 手法: EM (単粒子) / 解像度: 2.8 Å 40915 8szg EMDB-40915, PDB-8szg: Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.6 Å 40916 8szh EMDB-40916, PDB-8szh: Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.1 Å 40917 8szi EMDB-40917, PDB-8szi: Cryo-EM structure of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-41908: Local refinement map on VFT-CRD of active-state CaSR in lipid nanodiscs 手法: EM (単粒子) / 解像度: 2.6 Å EMDB-41909: Consensus refinement map of active-state human CaSR in lipid nanodiscs 手法: EM (単粒子) / 解像度: 2.8 Å EMDB-41910: Local refinement map on CRD-7TM of active-state CaSR in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-41925: Local refinement map on VFT-CRD of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 2.8 Å EMDB-41926: Local refinement map on Gi of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-41927: Local refinement map on CRD-7TM of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.2 Å EMDB-41928: Consensus refinement map of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-41949: Consensus refinement map of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-41950: Local refinement map on CRD-7TM of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.7 Å EMDB-41951: Local refinement map on VFT-CRD of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-41952: Local refinement map on Gq of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-41953: Consensus refinement map of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-41954: Local refinement map on VFT-CRD of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-41956: Local refinement map on CRD-7TM of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-41957: Local refinement map on Gi of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs 手法: EM (単粒子) / 解像度: 3.5 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-TRP: TRYPTOPHAN / 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 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 ChemComp-SPM: SPERMINE / スペルミン ChemComp-PCW: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / O-(1-O,2-O-ジオレオイル-L-グリセロ-3-ホスホ)コリン / DOPC, リン脂質YM ChemComp-CLR: CHOLESTEROL / コレステロ-ル ChemComp-HOH: WATER
由来	homo sapiens (ヒト)
キーワード	SIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein / Heterotrimeric G protein / Cryo-EM