期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 12, 页码 1150-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0152-y
关键词
-
资金
- Research Acceleration Program of the JST
- Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- JSPS-NSF International Collaboration in Chemistry (ICC)
- Takeda Science Foundation
- Japan Agency for Medical Research and Development (AMED)
- JSPS KAKENHI [15K08268, 15H06862]
- ImPACT Program of the Council for Science, Technology and Innovation (Cabinet Office, Government of Japan)
- NIH [R01-GM097261]
- Grants-in-Aid for Scientific Research [15K08268, 15H06862] Funding Source: KAKEN
Human muscarinic receptor M-2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M-2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M-2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M-2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M-2 receptors compared to M-3 receptors leads to subtype selectivity of AF-DX 384.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据