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-Structure paper
タイトル | Cryo-EM structures of orphan GPR21 signaling complexes. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 216, Year 2023 |
掲載日 | 2023年1月13日 |
著者 | Xi Lin / Bo Chen / Yiran Wu / Yingqi Han / Ao Qi / Junyan Wang / Zhao Yang / Xiaohu Wei / Tingting Zhao / Lijie Wu / Xin Xie / Jinpeng Sun / Jie Zheng / Suwen Zhao / Fei Xu / |
PubMed 要旨 | GPR21 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for type 2 diabetes and other metabolic disorders. This receptor shows high basal activity in coupling ...GPR21 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for type 2 diabetes and other metabolic disorders. This receptor shows high basal activity in coupling to multiple G proteins in the absence of any known endogenous agonist or synthetic ligand. Here, we present the structures of ligand-free human GPR21 bound to heterotrimeric miniGs and miniG15 proteins, respectively. We identified an agonist-like motif in extracellular loop 2 (ECL2) that occupies the orthosteric pocket and promotes receptor activation. A side pocket that may be employed as a new ligand binding site was also uncovered. Remarkably, G protein binding is accommodated by a flexible cytoplasmic portion of transmembrane helix 6 (TM6) which adopts little or undetectable outward movement. These findings will enable the design of modulators for GPR21 for understanding its signal transduction and exploring opportunity for deorphanization. |
リンク | Nat Commun / PubMed:36639690 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.12 - 3.8 Å |
構造データ | EMDB-33480: GPR21_m5_Gs EMDB-33481, PDB-8hj2: EMDB-33482, PDB-8hj0: EMDB-33483, PDB-8hj1: |
由来 |
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キーワード | STRUCTURAL PROTEIN (タンパク質) / GPCR (Gタンパク質共役受容体) / Orphan Receptor (オーファン受容体) |