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深入研究红氨酸乙酶C中的宏类结合亲缘关系和相关结构调节:洞察金星飞机制

Abhishek Bera¹, Pritish Joshi¹, Niladri Patra¹

¹Department of Chemistry & Chemical Biology, Indian Institute of Technology (ISM) Dhanbad, Dhanbad 826004, India.

Journal of chemical information and modeling

|November 20, 2024

概括

红红素化酶C (EreC) 与类抗生素 (如阿兹罗密和克拉里斯罗密) 相比,更强烈地与类抗生素结合. 这种相互作用涉及关键的疏水性残留物和类似"金星"的抵抗机制.

科学领域:

生物化学生物化学
分子生物学分子生物学
结构生物学结构生物学

背景情况:

宏类抗生素对于治疗细菌感染至关重要.
致病细菌进化抗微生物耐药性 (AMR) 机制,包括类酶.
氨酸乙酶C (EreC) 通过解它们的乳环来排毒化物.

研究的目的:

调查EreC与FDA批准的三种宏类物质之间的相互作用和构造动力学:红红素,清红素和亚红素.
阐明这些宏类的结合机制和它们与EreC.的亲缘关系.
了解由EreC介导的宏类抗性的结构基础.

主要方法:

经典的分子动力学模拟.
绝对具有约束力的自由能量计算使用简化化学自由能量扰乱 (SAFEP) 协议.
2D高温度元动力学模拟和基于图形理论的自向量中心性分析.

主要成果:

在EreC结合裂和小叶波动中的疏水性相互作用对宏化物结合至关重要.
在基氨酸扫描中,PHE248,MET333和PHE344被确定为化物结合的关键水性残留物.
与红红素相比,阿齐思罗米和克拉里思罗米对EreC具有更高的结合亲和力.
在EreC的活跃循环关闭过程中观察到一个转移稳定的"半开放"状态,类似于由HIS289的结构变化引发的"金星"机制.

结论:

EreC采用疏水性相互作用和动态结构变化来结合化物和水解.
结合亲和力的差异表明,宏类对EreC介导的耐药性的敏感性各不相同.
鉴定到的类似于"金星飞"的机制,提供了对EreC在对宏结合的反应中的构造动态的见解.

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