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Structure paper

タイトル	Promiscuous G-protein activation by the calcium-sensing receptor.
ジャーナル・号・ページ	Nature, Vol. 629, Issue 8011, Page 481-488, Year 2024
掲載日	2024年4月17日
著者	Hao Zuo / Jinseo Park / Aurel Frangaj / Jianxiang Ye / Guanqi Lu / Jamie J Manning / Wesley B Asher / Zhengyuan Lu / Guo-Bin Hu / Liguo Wang / Joshua Mendez / Edward Eng / Zhening Zhang / Xin Lin / Robert Grassucci / Wayne A Hendrickson / Oliver B Clarke / Jonathan A Javitch / Arthur D Conigrave / Qing R Fan /
PubMed 要旨	The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca concentration and maintains Ca homeostasis. It also mediates diverse cellular processes not associated with Ca ...The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca concentration and maintains Ca homeostasis. It also mediates diverse cellular processes not associated with Ca balance. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes. We determined structures of CaSR in complex with G proteins from three different subfamilies: G, G and G. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines G and G versus G selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.
リンク	Nature / PubMed:38632411
手法	EM (単粒子)
解像度	2.9 - 4.0 Å
構造データ	43811 9asb EMDB-43811, PDB-9asb: Structure of human calcium-sensing receptor in complex with chimeric Gq (miniGisq) protein in nanodiscs 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-43836: Consensus map of human CaSR-miniGisq complex in nanodiscs 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-43837: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-43840: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43841: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.7 Å EMDB-43897: Consensus map of human CaSR-miniGis complex in nanodiscs 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-43898: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGis complex 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-43899: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGis complex 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-43900: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGis complex 手法: EM (単粒子) / 解像度: 4.0 Å 43901 9avg EMDB-43901, PDB-9avg: Structure of human calcium-sensing receptor in complex with chimeric Gs (miniGis) protein in nanodiscs 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-43904: Consensus map of human CaSR-Gi3 complex in nanodiscs 手法: EM (単粒子) / 解像度: 3.8 Å EMDB-43905: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-Gi3 complex 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-43906: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-Gi3 complex 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-43907: Local refinement map of G protein in nanodisc-reconstituted human CaSR-Gi3 complex 手法: EM (単粒子) / 解像度: 3.3 Å 43908 9avl EMDB-43908, PDB-9avl: Structure of human calcium-sensing receptor in complex with Gi3 protein in nanodiscs 手法: EM (単粒子) / 解像度: 3.8 Å EMDB-43961: Consensus map of human CaSR-miniGisq complex in detergent 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-43962: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-43963: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-43964: Local refinement map of G protein in detergent-solubilized human CaSR-miniGisq complex 手法: EM (単粒子) / 解像度: 3.1 Å 43966 9axf EMDB-43966, PDB-9axf: Structure of human calcium-sensing receptor in complex with chimeric Gq (miniGisq) protein in detergent 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-43986: Consensus map of human CaSR-miniGi1 complex in detergent 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-43987: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGi1 complex 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-43988: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGi1 complex 手法: EM (単粒子) / 解像度: 3.6 Å EMDB-43989: Local refinement map of G protein in detergent-solubilized human CaSR-miniGi1 complex 手法: EM (単粒子) / 解像度: 3.2 Å 43990 9ayf EMDB-43990, PDB-9ayf: Structure of human calcium-sensing receptor in complex with Gi1 (miniGi1) protein in detergent 手法: EM (単粒子) / 解像度: 3.6 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 / N-アセチルグルコサミン ChemComp-TCR: CYCLOMETHYLTRYPTOPHAN / 1,2,3,4-テトラヒドロ-β-カルボリン-3α-カルボン酸 ChemComp-PO4: PHOSPHATE ION / ホスファ-ト / リン酸塩 ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-9IG: 3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propan-1-amine / NPS-R-568 ChemComp-Y01: CHOLESTEROL HEMISUCCINATE / コレステリルヘミスクシナ-ト PDB-1af7: CHER FROM SALMONELLA TYPHIMURIUM ChemComp-AV0: Lauryl Maltose Neopentyl Glycol / ラウリルマルト-スネオペンチルグリコ-ル ChemComp-CLR: CHOLESTEROL / コレステロ-ル / コレステロール
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ) lama glama (ラマ)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / Calcium-sensing receptor (カルシウム感知受容体) / G-protein-coupled receptor (Gタンパク質共役受容体) / G protein (Gタンパク質) / signal transduction (シグナル伝達)