Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35.
Insights into divalent cation regulation and G(13)-coupling of orphan receptor GPR35.
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深入了解孤儿受体 GPR35 的二价阳离子调节和 G13 偶联
DOI：
10.1038/s41421-022-00499-8
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发表时间：
2022-12-21
期刊：
影响因子：
33.5
通讯作者：
Jiang, Yi
中科院分区：
文献类型：
--
作者：
Duan, Jia;Liu, Qiufeng;Yuan, Qingning;Ji, Yujie;Zhu, Shengnan;Tan, Yangxia;He, Xinheng;Xu, Youwei;Shi, Jingjing;Cheng, Xi;Jiang, Hualiang;Eric Xu, H.;Jiang, Yi
内源性离子在G蛋白偶联受体（GPCRs）的功能和药理学中起着重要作用，但原子证据有限。此外，与Gs、Gi/o、Gq/11等G蛋白亚型相比，GPCR对G12/13蛋白偶联机制的研究缺乏足够的结构证据。孤儿受体GPR 35主要表达于胃肠道，与炎症性肠病（IBD）密切相关，是研究离子调节和G13偶联的典型受体。在这里，我们报告的冷冻电镜结构G13耦合GPR 35绑定到抗过敏药物，洛度沙胺。这种结构揭示了一种新的二价阳离子配位位点和独特的离子调节模式的GPR 35，也提出了一个高度带正电荷的结合口袋和互补的静电配体识别模式，这解释了混杂的酸性配体结合GPR 35。GPR 35-G13复合物与其他G蛋白亚型偶联的GPCR的结构比较显示，Gα 13亚基的α5螺旋的C-末端向受体核心显著移动，GPR 35-TM 6的胞质末端向外位移最少。一个特征性的“蛋氨酸口袋”有助于通过GPR 35偶联G13。总之，我们的研究结果为GPR 35的二价阳离子调节、配体识别和随后的G13蛋白偶联提供了结构基础，并为设计用于治疗IBD的GPR 35靶向药物提供了新的机会。
Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes Gs, Gi/o, and Gq/11, insufficient structural evidence is accessible to understand the coupling mechanism of G12/13protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel diseases (IBDs), stands out as a prototypical receptor for investigating ionic modulation and G13coupling. Here we report a cryo-electron microscopy structure of G13-coupled GPR35 bound to an anti-allergic drug, lodoxamide. This structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35 and also presents a highly positively charged binding pocket and the complementary electrostatic ligand recognition mode, which explain the promiscuity of acidic ligand binding by GPR35. Structural comparison of the GPR35–G13complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of α5 helix of the Gα13subunit towards the receptor core and the least outward displacement of the cytoplasmic end of GPR35 TM6. A featured ‘methionine pocket’ contributes to the G13coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G13protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.
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影响因子：
4.5
作者：
Atchison, Douglas K.;Beierwaltes, William H.
通讯作者：
Beierwaltes, William H.
影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
30.8
作者：
Imielinski, Marcin;Baldassano, Robert N.;Griffiths, Anne;Russell, Richard K.;Annese, Vito;Dubinsky, Marla;Kugathasan, Subra;Bradfield, Jonathan P.;Walters, Thomas D.;Sleiman, Patrick;Kim, Cecilia E.;Muise, Aleixo;Wang, Kai;Glessner, Joseph T.;Saeed, Shehzad;Zhang, Haitao;Frackelton, Edward C.;Hou, Cuiping;Flory, James H.;Otieno, George;Chiavacci, Rosetta M.;Grundmeier, Robert;Castro, Massimo;Latiano, Anna;Dallapiccola, Bruno;Stempak, Joanne;Abrams, Debra J.;Taylor, Kent;McGovern, Dermot;Heyman, Melvin B.;Ferry, George D.;Kirschner, Barbara;Lee, Jessica;Essers, Jonah;Grand, Richard;Stephens, Michael;Levine, Arie;Piccoli, David;Van Limbergen, Johan;Cucchiara, Salvatore;Monos, Dimitri S.;Guthery, Stephen L.;Denson, Lee;Wilson, David C.;Grant, Struan F. A.;Daly, Mark;Silverberg, Mark S.;Satsangi, Jack;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.4
作者：
Hu, Xiaohu;Provasi, Davide;Filizola, Marta
通讯作者：
Filizola, Marta