A MECHANISM FOR ROTAMASE CATALYSIS BY THE FK506 BINDING-PROTEIN (FKBP)
A MECHANISM FOR ROTAMASE CATALYSIS BY THE FK506 BINDING-PROTEIN (FKBP)
复制标题
DOI：
10.1021/bi00213a011
复制
发表时间：
1993-12-21
期刊：
影响因子：
2.9
通讯作者：
KARPLUS, M
中科院分区：
文献类型：
--
作者：
FISCHER, S;MICHNICK, S;KARPLUS, M
在已知的FK506/FKBP复合体结构模型的基础上，提出了FKBP酶催化Pro异构化的详细机理。模型底物通过脯氨酸转折结合为一种类型，末端暴露以允许更长的多肽链(例如，蛋白质环)作为底物。异构化的酰亚胺键的从头算势与体系其余部分的分子力学表示相结合来计算反应路径。由此得到的酶催化顺反异构化的活化能约为6千卡/摩尔，与实验结果吻合较好。相对于19kcal/mol的溶液，势垒的降低是由于酰亚胺羰基的脱溶、基态失稳、底物自催化和优先过渡态结合的共同作用。沿着反应路径，酶和底物中需要最小的重排。参与催化的酶残基与已有的突变数据一致。TYPE VIA TURN模型对应于蛋白质表面常见的序列特异性结构基序。它可能在与FKBP样结构域的蛋白质复合体的形成中发挥作用，这些结构域具有折叠酶或伴侣的功能。
A detailed mechanism for the catalysis of prolyl isomerization by the rotamase enzyme FKBP is proposed on the basis of a model constructed from the known structure of the FK506/FKBP complex. The model substrate is bound as a type VIa proline turn with the ends exposed to permit longer polypeptide chains (e.g., protein loops) to act as substrates. An ab initio potential for the isomerized imide bond is combined with a molecular mechanics representation of the rest of the system to calculate the reaction path. The resulting activation energy for the enzymatic cis --> trans isomerization is equal to about 6 kcal/mol, in good agreement with experiment. The lowering of the barrier relative to the solution value of 19 kcal/mol is found to arise from a combination of desolvation of the imide carbonyl, ground-state destabilization, substrate autocatalysis, and preferential transition-state binding. Minimal rearrangements are required in the enzyme and the substrate along the reaction path. The enzyme residues that participate in catalysis agree with the available mutation data. The type VIa turn model corresponds to a sequence-specific structural motif commonly found on the surface of proteins. It is likely to have a role in the formation of protein complexes with FKBP-like domains that function as foldases or chaperones.