新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » Nature报道 » Nature:解析出胰高血糖素受体的晶体结构有助开发出新的药物

Nature:解析出胰高血糖素受体的晶体结构有助开发出新的药物

来源:生物谷 2016-05-01 20:51

2016年5月1日/生物谷BIOON/--在一项新的研究中,在英国牛津郡同步加速器钻石光源发出的强X射线的帮助下获得的新结构信息能够让来自Heptares治疗公司(Heptares Therapeutics,是Sosei集团有限公司在英国的子公司)的研究人员解析出胰高血糖素受体的高分辨率X射线晶体结构。这种生物学受体在调节血糖水平中发挥着至关重要的作用,被认为是旨在开发治疗诸如糖尿病之类的代谢疾病的药物的重要靶标。相关研究结果于2016年4月25日在线发表在Nature期刊上,论文标题为“Extra-helical binding site of a glucagon receptor antagonist”。

Heptares治疗公司已利用这种强X射线解析出12多种G蛋白偶联受体(G protein-coupled receptor, GPCR)的结构,并且在此基础上设计出基于GPCR结构的StaR设计平台来开出诸如小分子和生物制剂之类的药物。

当前,Heptares治疗公司正在利用它在这种胰高血糖素受体上的开创性研究获得的结构和物理化学信息以及来自属于同类型的其他受体(B型GPCR)的结构和物理化学信息,加快将小分子GLP-1拮抗剂推向临床应用以便治疗一种罕见的疾病,即先天性高胰岛素血症。

在这项新的研究中,来自Heptares治疗公司的研究人员鉴定出这种胰高血糖素受体上的一个与胰高血糖素结合位点截然不同的新结合位点。这种“变构的(allosteric)”结合位点位于这种受体的跨膜结构域的外面,而且经证实当这种受体结合到小分子拮抗剂MK-0893上时,这种变构结合位点抑制这种受体的正常信号转导功能。

论文通信作者Fiona Marshall说,Heptares治疗公司继续证实它的StaR平台能够阐明重要的GPCR结构,并且将这种知识应用到它和它的合作伙伴的药物设计程序上。该公司的开创性研究极大地加强它应用它的基于结构的方法开发靶向一系列不同的GPCR靶标的药物的能力。

B型GPCR代表着结构类似的肽类激素(如GLP-1、胰高血糖素、促肾上腺皮质激素释放因子、降钙素和甲状旁腺激素)受体家族。B型GPCR包括针对心血管疾病、代谢疾病、骨科疾病和偏头痛的很多治疗靶标,但是尽管它们在临床上已得到强有力的验证,但是它们的结构信息仍然是有限的。(生物谷 Bioon.com)

本文系生物谷原创编译整理,欢迎转载!点击 获取授权 。更多资讯请下载生物谷APP

Extra-helical binding site of a glucagon receptor antagonist

doi:10.1038/nature17414

Ali Jazayeri, Andrew S. Doré, Daniel Lamb, Harini Krishnamurthy, Stacey M. Southall, Asma H. Baig, Andrea Bortolato, Markus Koglin, Nathan J. Robertson, James C. Errey, Stephen P. Andrews, Iryna Teobald, Alastair J. H. Brown, Robert M. Cooke, Malcolm Weir & Fiona H. Marshall

Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis1. Glucagon action is transduced by the class B G-protein-coupled glucagon receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations2. Although an X-ray structure of the transmembrane domain of the GCGR3 has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that glucagon activation of the receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B receptors is limited, with only one other ligand-binding site defined—for the corticotropin-releasing hormone receptor 1 (CRF1R)—which was located deep within the 7TM bundle5. We describe a completely novel allosteric binding site for class B receptors, providing an opportunity for structure-based drug design for this receptor class and furthering our understanding of the mechanisms of activation of these receptors.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库