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上海药物所徐华强和王明伟课题组发现B型GPCR激活新机制

时间: 2017-04-03 21:24 字号:|| 点击:
摘要:中国科学院上海药物研究所徐华强课题组与王明伟课题组通过合作研究,最近发现了B型G蛋白偶联受体(G protein-coupled receptor, GPCR)新的激活机制。

        中国科学院上海药物研究所徐华强课题组与王明伟课题组通过合作研究,最近发现了B型G蛋白偶联受体(G protein-coupled receptor, GPCR)新的激活机制。该成果3月29日在线发表于国际学刊The Journal of Biological Chemistry,题为“Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors”。殷艳婷博士为论文第一作者,徐华强研究员和王明伟研究员为共同通讯作者。

        B型分泌素GPCR家族由15个肽类激素受体组成,包括胰高血糖素受体、血管活性肠肽受体、胰高血糖素样肽受体和甲状旁腺激素受体等,在体内激素平衡调节中发挥关键作用,是治疗骨类疾病、代谢性疾病和神经系统疾病的重要药物作用靶标。由于目前对该家族受体的激活机制及构象变化知之甚少,基于其下游信号通路的药物开发举步维艰。

        该研究中以胰高血糖素受体为模式,提出了其激活的分子机制,即受体第六跨膜区被保守极性口袋和疏水区域限制在非活性构象,破坏这两个关键结构域会使第六跨膜区的构象发生改变从而产生自我激活效应。研究还发现,该保守极性口袋的重组也会导致其他B型GPCR(如血管活性肠肽受体I、促肾上腺皮质激素释放因子受体I、甲状旁腺激素受体I和垂体腺苷酸环化酶激活多肽受体I等)的自我激活,说明重组该保守极性口袋为B型GPCR的共有激活机制。

        这个成果也解释了人们20年前所观察到的现象,即为何甲状旁腺激素受体中的双位点突变会引起受体发生自我激活而导致Jansen‘s Metaphyseal Chondrodysplasia(一种先天性软骨发育异常症)。

 

 

BGPCRTM2TM3TM6TM7的保守氨基酸通过形成极性口袋来稳定受体的未激活构象。

论文链接

Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors

论文摘要

The glucagon receptor (GCGR) belongs to the secretin-like (class B) family of G protein-coupled receptors (GPCRs) and is activated by the peptide hormone, glucagon. The structures of an activated class B GPCR have remained unsolved, preventing a mechanistic understanding of how these receptors are activated. Using a combination of structural modeling and mutagenesis studies, we present here two modes of ligand-independent activation of GCGR. First, we identified a GCGR-specific hydrophobic lock comprising M338 and F345 within the IC3 loop and transmembrane helix 6 (TM6) and found that this lock stabilizes the TM6 helix in the inactive conformation. Disruption of this hydrophobic lock led to constitutive G protein and arrestin signaling. Second, we discovered a polar core comprising conserved residues in TM2, TM3, TM6, and TM7, and mutations that disrupt this polar core led to constitutive GCGR activity. On the basis of these results, we propose a mechanistic model of GCGR activation, in which TM6 is held in an inactive conformation by the conserved polar core and the hydrophobic lock. Mutations that disrupt these inhibitory elements allow TM6 to swing outwards to adopt an active TM6 conformation similar to that of the canonical β2 adrenergic receptor complexed with G protein and to that of rhodopsin complexed with arrestin. Importantly, mutations in the corresponding polar core of several other members of class B GPCRs, including PTH1R, PAC1R, VIP1R, and CRFR1, also induce constitutive G protein signaling, suggesting that the rearrangement of the polar core is a conserved mechanism for class B GPCR activation.

(http://www.jbc.org/cgi/doi/10.1074/jbc.M117.782987)

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