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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Enzyme Flexibility and the Catalytic Mechanism of Farnesyltransferase: Targeting the Relation
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Enzyme Flexibility and the Catalytic Mechanism of Farnesyltransferase: Targeting the Relation

机译：酶的柔韧性和法呢基转移酶的催化机制：针对关系。

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摘要

Farnesyltransferase enzyme (FTase) is an interesting target for anticancer therapy that has been the subject of particular attention over the past decade. However, despite of the thrilling achievements in the development of farnesyltransferase inhibitors (FTIs) over the past few years, the farnesylation mechanism remains, to some degree, a mystery. This work describes the application of molecular dynamics simulations to the study of enzyme flexibility in the 4 key intermediate states formed during the FTase catalytic mechanism—FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-Peptide), and product complex (FTase-Product)—thereby covering the main states in the mechanistic pathway of this mysterious enzyme, while relating, dissecting, and exploring, in minute detail, the set of structural and dynamical changes taking place with FPP binding, peptide coordination and product formation. This study reveals the existence of a series of variational patterns involving the mechanistic events taking place at the active site of the enzyme, increasing in magnitude away from the active-site, demonstrating that relatively small-scale events such as substrate binding or product formation cause minor changes at the neighboring residues and corresponding helices, but ultimately induce much more dramatic effects on the more external regions of the enzyme.
机译：法呢基转移酶（FTase）是抗癌治疗的一个有趣目标，在过去十年中一直受到特别关注。然而，尽管在过去几年中在法呢基转移酶抑制剂（FTI）的开发方面取得了令人鼓舞的成就，但法呢基化机制在一定程度上仍是一个谜。这项工作描述了分子动力学模拟在研究FTase催化机理过程中形成的4个关键中间状态（FTase静止状态，二元复合物（FTase-FPP），三元复合物（FTase-FPP-肽），和产物复合物（FTase-Product）-从而涵盖了这种神秘酶的机理途径中的主要状态，同时与FPP结合，肽配位发生的结构和动力学变化有关，并进行了详细的探讨。和产品形成。这项研究揭示了一系列变化模式的存在，这些变化模式涉及在酶的活性位点发生的机械事件，其幅度从活性位点开始逐渐增加，这表明相对较小规模的事件（例如底物结合或产物形成）会导致在相邻残基和相应的螺旋上发生微小变化，但最终会对酶的更多外部区域产生更大的影响。

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