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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Interactions of oximino-substituted boronic acids and β-lactams with the cmy-2-derived extended-spectrum cephalosporinases cmy- 30 and cmy-42
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Interactions of oximino-substituted boronic acids and β-lactams with the cmy-2-derived extended-spectrum cephalosporinases cmy- 30 and cmy-42

机译:肟基取代的硼酸和β-内酰胺与cmy-2衍生的广谱头孢菌病cmy-30和cmy-42的相互作用

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摘要

CMY-30 and CMY-42 are extended-spectrum (ES) derivatives of CMY-2. ES characteristics are due to substitutions of Gly (CMY- 30) and Ser (CMY-42) for Val211 in theβ-loop. To characterize the effects of 211 substitutions, we studied the interactions of CMY-2, -30, and -42 with boronic acid transition state inhibitors (BATSIs) resembling ceftazidime and cefotaxime, assessed thermal stability of the enzymes in their free forms and in complexes with BATSIs and oximino lactams, and simulated, using molecular dynamics (MD), the CMY-42 apoenzyme and the CMY-42 complexes with ceftazidime and the ceftazidime-like BATSI. Inhibition constants showed that affinities between CMY-30 and CMY-42 and the R1 groups of BATSIs were lower than those of CMY-2. ES variants also exhibited decreased thermal stability either as apoenzymes or in covalent complexes with oximino compounds.MDsimulations further supported destabilization of the ES variants. Val211Ser increased thermal factors of theloop backbone atoms, as previously observed for CMY-30. The similar effects of the two substitutions seemed to be due to a less-constrained Tyr221 likely inducing concerted movement of elements at the edges of the active site (loop-Q120 loop-R2 loop/H10 helix). This inner-protein movement, along with the wider R1 binding cleft, enabled intense vibrations of the covalently bound ceftazidime and ceftazidime-like BATSIs. Increased flexibility of the ES enzymes may assist the productive adaptation of the active site to the various geometries of the oximino substrates during the reaction (higher frequency of near-attack conformations).
机译:CMY-30和CMY-42是CMY-2的扩展光谱(ES)衍生物。 ES特性是由于β-环中的Val211被Gly(CMY-30)和Ser(CMY-42)取代。为了表征211取代的影响,我们研究了CMY-2,-30和-42与类似于头孢他啶和头孢噻肟的硼酸过渡态抑制剂(BATSI)的相互作用,评估了酶的游离形式和复合物的热稳定性。用BATSI和oximino内酰胺进行模拟,并使用分子动力学(MD)模拟CMY-42脱辅酶和CMY-42与头孢他啶和类似头孢他啶的BATSI的复合物。抑制常数表明,CMY-30和CMY-42与BATSI的R1组之间的亲和力低于CMY-2。 ES变体还表现出降低的热稳定性,无论是作为脱辅酶还是与肟基化合物共价配合。MD模拟进一步支持了ES变体的去稳定作用。 Val211Ser增加了环骨架原子的热因子,如先前对CMY-30观察到的。两次取代的相似作用似乎是由于较少的Tyr221约束可能导致在活性位点(loop-Q120 loop-R2 loop / H10螺旋)边缘的元素协同运动。这种内部蛋白质运动,加上更宽的R1结合裂隙,使共价结合的头孢他啶和头孢他啶样BATSI剧烈振动。 ES酶增加的柔韧性可以帮助反应期间活性位点适应肟基底物的各种几何形状(较高频率的近攻击构象)。

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