Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces.
Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces.
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DOI：
10.1021/ci300175u
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发表时间：
2012-08-27
影响因子：
5.6
通讯作者：
Kozakov D
中科院分区：
文献类型：
--
作者：
Zerbe BS;Hall DR;Vajda S;Whitty A;Kozakov D
在蛋白质-蛋白质相互作用的上下文中，术语“热点”是指对结合自由能做出主要贡献的残基或残基簇，如通过丙氨酸扫描诱变测定的。相反，在药物研究中，热点是靶蛋白上具有高配体结合倾向的位点，因此对药物发现具有潜在的重要性。在这里，我们研究这两个热点概念之间的关系，通过比较丙氨酸扫描数据的一组15个蛋白质的结果，从映射的蛋白质表面的网站，可以结合片段大小的小分子。我们发现这两种类型的热点在很大程度上是互补的，通过计算映射或实验片段筛选确定的突出到热点区域的残基几乎总是由丙氨酸扫描实验定义的热点残基。相反，通过丙氨酸扫描发现的对结合贡献很小的残基很少与通过片段作图鉴定的伴侣蛋白上的热点区域相互作用。尽管这两个热点概念之间有很强的相关性，但它们有根本的不同。特别地，虽然通过丙氨酸扫描鉴定热点建立了与结合配偶体产生大量相互作用能的潜力，但对于小分子结合的热点存在额外的拓扑要求。因此，通过丙氨酸扫描鉴定的热点中只有少数代表对小抑制剂结合潜在有用的位点，并且通过实验或计算片段筛选鉴定的正是该子集。
In the context of protein-protein interactions, the term “hot spot” refers to a residue or cluster of residues that makes a major contribution to the binding free energy, as determined by alanine scanning mutagenesis. In contrast, in pharmaceutical research a hot spot is a site on a target protein that has high propensity for ligand binding and hence is potentially important for drug discovery. Here we examine the relationship between these two hot spot concepts by comparing alanine scanning data for a set of 15 proteins with results from mapping the protein surfaces for sites that can bind fragment-sized small molecules. We find the two types of hot spots are largely complementary; the residues protruding into hot spot regions identified by computational mapping or experimental fragment screening are almost always themselves hot spot residues as defined by alanine scanning experiments. Conversely, a residue that is found by alanine scanning to contribute little to binding rarely interacts with hot spot regions on the partner protein identified by fragment mapping. In spite of the strong correlation between the two hot spot concepts, they fundamentally differ, however. In particular, while identification of a hot spot by alanine scanning establishes the potential to generate substantial interaction energy with a binding partner, there are additional topological requirements to be a hot spot for small molecule binding. Hence, only a minority of hot spots identified by alanine scanning represent sites that are potentially useful for small inhibitor binding, and it is this subset that is identified by experimental or computational fragment screening.
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DOI：
10.1073/pnas.062398499
发表时间：
2002-04-02
影响因子：
11.1
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
通讯作者：
Vajda, S
影响因子：
2.9
作者：
Gordon, NC;Pan, B;Starovasnik, MA
通讯作者：
Starovasnik, MA
影响因子：
7.3
作者：
Boehm, HJ;Boehringer, M;Meunier-Keller, N
通讯作者：
Meunier-Keller, N
DOI：
10.1038/nsb0295-171
发表时间：
1995-02-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
CASARI, G;SANDER, C;VALENCIA, A
通讯作者：
VALENCIA, A
影响因子：
5.6
作者：
Buhrman, Greg;O'Connor, Casey;Zerbe, Brandon;Kearney, Bradley M.;Napoleon, Raeanne;Kovrigina, Elizaveta A.;Vajda, Sandor;Kozakov, Dima;Kovrigin, Evgenii L.;Mattos, Carla
通讯作者：
Mattos, Carla