Mechanistic insight into the role of transition-state stabilization in cyclophilin A.
Mechanistic insight into the role of transition-state stabilization in cyclophilin A.
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DOI：
10.1021/ja806146g
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发表时间：
2009-01-14
影响因子：
15
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Hamelberg, Donald;McCammon, J. Andrew
肽基脯氨酰顺-反异构酶（PPIases）是生物学中普遍存在的酶，催化许多细胞信号传导途径中脯氨酸酰亚胺肽键的顺-反异构化。脯氨酰肽键异构状态的局部变化作为改变蛋白质构象的转换机制。对PPIases的机制仍然缺乏完整的理解，目前的实验技术还不能提供详细的原子图。在这里，我们进行了几个加速分子动力学模拟与明确的溶剂，我们提供了一个详细的描述的顺反异构化的自由和亲环素A催化的过程。我们表明，亲环素的催化机制主要是由于稳定和优先结合的过渡态，这是通过一个有利的氢键与骨架NH基团的相互作用。我们还表明，在过渡态的底物更有利地与酶的相互作用比顺式异构体，这反过来又比反式异构体更有利地相互作用。酶-底物复合物的稳定性与底物与高度保守的精氨酸残基的相互作用直接相关。最后，我们表明，催化是通过旋转的脯氨酰肽键的N-末端上的羰基氧主要是单向的方式实现的。
Peptidyl prolyl cis−trans isomerases (PPIases) are ubiquitous enzymes in biology that catalyze the cis−trans isomerization of the proline imide peptide bond in many cell signaling pathways. The local change of the isomeric state of the prolyl peptide bond acts as a switching mechanism in altering the conformation of proteins. A complete understanding of the mechanism of PPIases is still lacking, and current experimental techniques have not been able to provide a detailed atomistic picture. Here we have carried out several accelerated molecular dynamics simulations with explicit solvent, and we have provided a detailed description of cis−trans isomerization of the free and cyclophilin A-catalyzed process. We show that the catalytic mechanism of cyclophilin is due mainly to the stabilization and preferential binding of the transition state that is achieved by a favorable hydrogen bond interaction with a backbone NH group. We also show that the substrate in the transition state interacts more favorably with the enzyme than the cis isomer, which in turn interacts more favorably than the trans isomer. The stability of the enzyme−substrate complex is directly correlated with the interaction the substrate makes with a highly conserved arginine residue. Finally, we show that catalysis is achieved through the rotation of the carbonyl oxygen on the N-terminal of the prolyl peptide bond in a predominately unidirectional fashion.
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影响因子：
2.4
作者：
GRUBMULLER, H
通讯作者：
GRUBMULLER, H
影响因子：
15
作者：
Hur, S;Bruice, TC
通讯作者：
Bruice, TC
DOI：
10.1038/nsb927
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Howard, BR;Vajdos, FF;Hill, CP
通讯作者：
Hill, CP
影响因子：
64.8
作者：
Eisenmesser, EZ;Millet, O;Kern, D
通讯作者：
Kern, D
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML