期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 8, 页码 3572-3581出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00137
关键词
-
资金
- European Union [LSH-2005-2.2.0-8]
- Klaus Tschira Foundation [AIRC IG 10474]
- Alexander von Humboldt Foundation
- Finnish Cultural Foundation
- Academy of Finland
- University of Eastern Finland
- NIH [GM-24485]
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate K-M values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface.
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