Science Blog of Dr. Yuan分享 http://blog.sciencenet.cn/u/albumns This blog is mainly on Molecular molecular modelling and simulations

博文

Exploring a new ligand binding site of GPCR by MD simulation

已有 4054 次阅读 2018-7-17 22:33 |个人分类:未分类|系统分类:科研笔记

Chemical Science (2018) doi: 10.1039/C8SC01680A

full text 

Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcho-line receptors. Our results indicate that unlike the synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket. We also discovered that the most recently resolved crystal structure of LTB4 receptor comprised a bound inverse agonist, which extended its benzamidine moiety to the same binding pocket discovered in this work. Analysis on all resolve GPCR crystal structures indicated that this new pocket could exist in most receptors. Our findings provide new opportunities for GPCR drug discovery.



The relative positions of the classic orthosteric site (yellow shaded sphere) and the newly discovered novel ligand binding site(left panel, red shaded sphere) located between W6.48 an D2.50. A new drug molecule (right panel) can be designed, based on the newly discovered site in this work. Green balls-and-sticks: TTP molecule observed in the crystal structures of M3 & M4 receptors. Yellow balls-and-sticks: ACh observed in this work. Cyan stick: an inverse agonist observed in the crystal structure of LTB4 receptor.





https://blog.sciencenet.cn/blog-355217-1124563.html

上一篇:First GPCR-directed antibody passes approval milestone
下一篇:The first Frizzled class GPCR structure was resolved
收藏 IP: 212.203.114.*| 热度|

0

该博文允许注册用户评论 请点击登录 评论 (0 个评论)

数据加载中...

Archiver|手机版|科学网 ( 京ICP备07017567号-12 )

GMT+8, 2024-3-19 14:11

Powered by ScienceNet.cn

Copyright © 2007- 中国科学报社

返回顶部