Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology.
Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology.
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DOI：
10.1016/j.celrep.2018.02.085
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发表时间：
2018-03-20
期刊：
影响因子：
8.8
通讯作者：
Marsh JA
中科院分区：
文献类型：
--
作者：
Abrusán G;Marsh JA
有人认为，蛋白质复合物的进化受到随机、非适应性过程的显著影响。使用配体结合作为功能的代理，我们表明配体结合位点的结构显著影响蛋白质复合物的进化。结果表明，具有多链结合位点（mbs）的同聚体比单体或其他同聚体进化新功能的速度慢，其结合辅因子和金属具有比其他同聚体更保守的四级结构。此外，与单体和其他同源异构体相比，同源MBS的配体和配体结合袋更相似。我们的研究结果表明，在辅助因子结合的MBS同源物中，四级结构的进化选择很强，而在具有单链结合位点的配合物中，中性过程更为重要。它们还具有药理意义，表明具有单链结合位点的复合物是选择性药物的更好靶点，而MBS同质体是广谱抗生素和多靶点药物设计的良好候选者。配体结合位点结构显著影响蛋白质功能进化MBS同型体比单体和其他同型体具有更相似的配体结合袋，辅助因子和金属结合的MBS同型体比其他同型体具有更保守的QS。MBS同型体是开发抗生素和多靶点药物的有希望的靶点，具有涉及多蛋白链的配体结合位点（MBS同型体）的新功能进化速度比其他同型体和单体慢。结合辅因子/金属的辅因子也具有更保守的四级结构（QS）。这些复合物很可能成为抗生素和多靶点药物的有希望的靶点。
It has been suggested that the evolution of protein complexes is significantly influenced by stochastic, non-adaptive processes. Using ligand binding as a proxy of function, we show that the structure of ligand-binding sites significantly influences the evolution of protein complexes. We show that homomers with multi-chain binding sites (MBSs) evolve new functions slower than monomers or other homomers, and those binding cofactors and metals have more conserved quaternary structure than other homomers. Moreover, the ligands and ligand-binding pockets of homologous MBS homomers are more similar than monomers and other homomers. Our results suggest strong evolutionary selection for quaternary structure in cofactor-binding MBS homomers, whereas neutral processes are more important in complexes with single-chain binding sites. They also have pharmacological implications, suggesting that complexes with single-chain binding sites are better targets for selective drugs, whereas MBS homomers are good candidates for broad-spectrum antibiotic and multitarget drug design. Ligand binding site structure significantly influences protein function evolution MBS homomers have more similar ligand binding pockets than monomers and other homomers Cofactor and metal-binding MBS homomers have more conserved QS than other homomers MBS homomers are promising targets for developing antibiotics and multitarget drugs Homomers with ligand binding sites involving multiple protein chains (MBS homomers) evolve new functions slower than other homomers and monomers, and the ones binding cofactors/metals also have more conserved quaternary structure (QS). These complexes are likely to be promising targets for antibiotics and multitarget drugs.
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影响因子：
56.9
作者：
Lynch, M;Conery, JS
通讯作者：
Conery, JS
影响因子：
11.4
作者：
Capra, John A.;Stolzer, Maureen;Durand, Dannie;Pollard, Katherine S.
通讯作者：
Pollard, Katherine S.
影响因子：
14.9
作者：
Kim, DE;Chivian, D;Baker, D
通讯作者：
Baker, D
DOI：
10.1073/pnas.1310980110
发表时间：
2013-07-23
影响因子：
11.1
作者：
Lynch, Michael
通讯作者：
Lynch, Michael
影响因子：
4.6
作者：
Bergendahl LT;Marsh JA
通讯作者：
Marsh JA