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-Structure paper
タイトル | Promiscuous G-protein activation by the calcium-sensing receptor. |
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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 | EMDB-43811, PDB-9asb: EMDB-43836: Consensus map of human CaSR-miniGisq complex in nanodiscs EMDB-43837: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGisq complex EMDB-43840: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGisq complex EMDB-43841: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGisq complex EMDB-43897: Consensus map of human CaSR-miniGis complex in nanodiscs EMDB-43898: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGis complex EMDB-43899: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGis complex EMDB-43900: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGis complex EMDB-43901, PDB-9avg: EMDB-43904: Consensus map of human CaSR-Gi3 complex in nanodiscs EMDB-43905: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-Gi3 complex EMDB-43906: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-Gi3 complex EMDB-43907: Local refinement map of G protein in nanodisc-reconstituted human CaSR-Gi3 complex EMDB-43908, PDB-9avl: EMDB-43961: Consensus map of human CaSR-miniGisq complex in detergent EMDB-43962: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGisq complex EMDB-43963: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGisq complex EMDB-43964: Local refinement map of G protein in detergent-solubilized human CaSR-miniGisq complex EMDB-43966, PDB-9axf: EMDB-43986: Consensus map of human CaSR-miniGi1 complex in detergent EMDB-43987: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGi1 complex EMDB-43988: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGi1 complex EMDB-43989: Local refinement map of G protein in detergent-solubilized human CaSR-miniGi1 complex EMDB-43990, PDB-9ayf: |
化合物 | ChemComp-NAG: ChemComp-TCR: ChemComp-PO4: ChemComp-CA: ChemComp-9IG: ChemComp-Y01: PDB-1af7: ChemComp-AV0: ChemComp-CLR: |
由来 |
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キーワード | MEMBRANE PROTEIN / Calcium-sensing receptor / G-protein-coupled receptor / G protein / signal transduction |