G蛋白偶联受体
药物发现
低温电子显微
计算生物学
药品
结构生物学
纳米技术
生物物理学
生物
受体
化学
计算机科学
生物信息学
材料科学
细胞生物学
生物化学
药理学
作者
Xin Zhang,Rachel M. Johnson,Ieva Drulyte,Lin Yu,Abhay Kotecha,Radostin Danev,Denise Wootten,Patrick M. Sexton,Matthew J. Belousoff
出处
期刊:Structure
[Elsevier]
日期:2021-09-01
卷期号:29 (9): 963-974.e6
被引量:25
标识
DOI:10.1016/j.str.2021.04.008
摘要
G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in stabilization of GPCR:transducer complexes, together with improvements in cryoelectron microscopy (cryo-EM) have recently been applied to structure-assisted drug design for GPCR agonists. Nonetheless, limitations in the commercial application of these approaches, including the use of nanobody 35 (Nb35) to aid complex stabilization and the high cost of 300 kV imaging, have restricted broad application of cryo-EM in drug discovery. Here, using the PF 06882961-bound GLP-1R as exemplar, we validated the formation of stable complexes with a modified Gs protein in the absence of Nb35. In parallel, we compare 200 versus 300 kV image acquisition using a Falcon 4 or K3 direct electron detector. Moreover, the 200 kV Glacios-Falcon 4 yielded a 3.2 Å map with clear density for bound drug and multiple structurally ordered waters. Our work paves the way for broader commercial application of cryo-EM for GPCR drug discovery.
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