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D类GPCR Ste2的结构获解析
2020-12-03 15:03

英国MRC分子生物学实验室Christopher G. Tate团队取得一项新突破。他们的最新研究解析了D类G蛋白偶联受体(GPCR)Ste2二聚体与两个G蛋白偶联的结构。2020年12月2日,《自然》在线发表了这项成果。

研究人员解析了D类GPCR的结构,即酿酒酵母信息素受体Ste2,其存在于异三聚体G蛋白Gpa1–Ste4–Ste18偶联的活跃结构中。纯化的Ste2是与两个G蛋白同型二聚体偶联形式存在。Ste2的二聚体界面由N末端、跨膜螺旋H1、H2和H7和第一个细胞外环ECL1组成。

研究人员建立了D1类通用残基编号系统(CD1),可以与直向同源物和其它类GPCR进行比较。Ste2的结构在总拓扑结构上与A类GPCR相似,但是跨膜螺旋H4的位移超过20Å,并且G蛋白结合位点位于浅沟而不是裂隙。该结构为靶向真菌GPCR的新药设计提供了参考,可用于治疗多种难治性真菌疾病。

研究人员表示,在系统发育学上GPCR可分为6类并以A至F表示。已解析了脊椎动物370多种GPCR的结构(属于A、B、C和F类),这有助于了解其功能。相比之下,没有D类GPCR的结构获解析,这些结构仅存在于真菌中,其可以调节真菌的存活和繁殖。

附:英文原文

Title: Structure of the class D GPCR Ste2 dimer coupled to two G proteins

Author: Vaithish Velazhahan, Ning Ma, Gspr Pndy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, Nagarajan Vaidehi, Christopher G. Tate

Issue&Volume: 2020-12-02

Abstract: G-protein-coupled receptors (GPCRs) are divided phylogenetically into six classes1,2, denoted A to F. More than 370 structures of vertebrate GPCRs (belonging to classes A, B, C and F) have been determined, leading to a substantial understanding of their function3. By contrast, there are no structures of class D GPCRs, which are found exclusively in fungi where they regulate survival and reproduction. Here we determine the structure of a class D GPCR, the Saccharomyces cerevisiae pheromone receptor Ste2, in an active state coupled to the heterotrimeric G protein Gpa1–Ste4–Ste18. Ste2 was purified as a homodimer coupled to two G proteins. The dimer interface of Ste2 is formed by the N terminus, the transmembrane helices H1, H2 and H7, and the first extracellular loop ECL1. We establish a class D1 generic residue numbering system (CD1) to enable comparisons with orthologues and with other GPCR classes. The structure of Ste2 bears similarities in overall topology to class A GPCRs, but the transmembrane helix H4 is shifted by more than 20 and the G-protein-binding site is a shallow groove rather than a cleft. The structure provides a template for the design of novel drugs to target fungal GPCRs, which could be used to treat numerous intractable fungal diseases4.

DOI: 10.1038/s41586-020-2994-1

Source: https://www.nature.com/articles/s41586-020-2994-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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