瑞士诺华生物医学研究所Veli-Pekka Jaakola、Klemens Kaupmann和Matthias Haffke等研究人员揭示了物种选择性拮抗剂与琥珀酸受体结合的结构基础。2019年10月24日出版的《自然》发表了这项成果。

研究人员报道了大鼠SUCNR1与非活性构象的胞内结合纳米抗体形成复合物后的高分辨率晶体结构。基于结构的诱变和放射性配体结合研究与分子建模相结合，研究人员确定了物种选择性拮抗剂结合的关键残基，并能够确定人源化大鼠SUCNR1与高亲和力的、人类选择性拮抗剂NF-56-EJ40形成复合物后的高分辨率晶体结构。研究人员认为，这些关于琥珀受体的结构及其拮抗剂选择性的认知将促进基于结构的药物发现，并且将有助于进一步阐明SUCNR1在体外和体内的功能。

据悉，三羧酸循环中间体琥珀酸参与代谢过程，并在线粒体活性氧的稳态中扮演了至关重要的作用。负责琥珀酸信号传导的受体SUCNR1（也称为GPR91）是G蛋白偶联受体家族的成员，并将琥珀酸信号与肾素引起的高血压、视网膜血管生成和炎症联系在一起。由于SUCNR1将琥珀酸感觉为一种免疫危险信号，它与溃疡性结肠炎、肝纤维化、糖尿病和类风湿性关节炎有关，因此它作为治疗靶标引起了人们的关注。

附：英文原文

Title: Structural basis of species-selective antagonist binding to the succinate receptor

Author: Matthias Haffke, Dominique Fehlmann, Gabriele Rummel, Jacques Boivineau, Myriam Duckely, Nina Gommermann, Simona Cotesta, Finton Sirockin, Felix Freuler, Amanda Littlewood-Evans, Klemens Kaupmann, Veli-Pekka Jaakola

Issue&Volume: 2019-10-23

Abstract: The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species1. The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family2 and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation3,4,5. Because SUCNR1 senses succinate as an immunological danger signal6—which has relevance for diseases including ulcerative colitis, liver fibrosis7, diabetes and rheumatoid arthritis3,8—it is of interest as a therapeutic target. Here we report the high-resolution crystal structure of rat SUCNR1 in complex with an intracellular binding nanobody in the inactive conformation. Structure-based mutagenesis and radioligand-binding studies, in conjunction with molecular modelling, identified key residues for species-selective antagonist binding and enabled the determination of the high-resolution crystal structure of a humanized rat SUCNR1 in complex with a high-affinity, human-selective antagonist denoted NF-56-EJ40. We anticipate that these structural insights into the architecture of the succinate receptor and its antagonist selectivity will enable structure-based drug discovery and will further help to elucidate the function of SUCNR1 in vitro and in vivo.

DOI: 10.1038/s41586-019-1663-8

Source: https://www.nature.com/articles/s41586-019-1663-8