双环分子
化学
鸟嘌呤核苷酸交换因子
肽
背景(考古学)
GTP酶
鸟嘌呤
G蛋白
配体(生物化学)
肽库
核苷酸
化学生物学
生物化学
计算生物学
立体化学
肽序列
受体
生物
古生物学
基因
作者
Anna Pepanian,Furkan Ayberk Binbay,Suchismita Roy,Britta Nubbemeyer,Amritendu Koley,Curran A. Rhodes,Hermann Ammer,Dehua Pei,Pradipta Ghosh,Diana Imhof
标识
DOI:10.1021/acs.jmedchem.3c00873
摘要
Noncanonical G protein activation and inactivation, particularly for the Gαi/s protein subfamilies, have long been a focus of chemical research. Combinatorial libraries were already effectively applied to identify modulators of the guanine-nucleotide exchange, as can be exemplified with peptides such as KB-752 and GPM-1c/d, the so-called guanine-nucleotide exchange modulators. In this study, we identified novel bicyclic peptides from a combinatorial library screening that show prominent properties as molecular switch-on/off modulators of Gαi signaling. Among the series of hits, the exceptional paradigm of GPM-3, a protein and state-specific bicyclic peptide, is the first chemically identified GAP (GTPase-activating protein) modulator with a high binding affinity for Gαi protein. Computational analyses identified and assessed the structure of the bicyclic peptides, novel ligand–protein interaction sites, and their subsequent impact on the nucleotide binding site. This approach can therefore lead the way for the development of efficient chemical biological probes targeting Gαi protein modulation within a cellular context.
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