Dynamical Behavior of β-Lactamases and Penicillin- Binding Proteins in Different Functional States and Its Potential Role in Evolution
Dynamical Behavior of β-Lactamases and Penicillin- Binding Proteins in Different Functional States and Its Potential Role in Evolution
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DOI：
10.3390/e21111130
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发表时间：
2019-11-19
期刊：
影响因子：
2.7
通讯作者：
Tao P
中科院分区：
文献类型：
--
作者：
Wang F;Zhou H;Wang X;Tao P
β-内酰胺酶是由细菌产生的水解β-内酰胺类抗生素的酶，通过相关抗生素耐药性对公众健康构成严重威胁。A类β-内酰胺酶在结构和功能上与青霉素结合蛋白（PBP）相关。尽管对β-内酰胺酶和PBPs的结构、催化机制和动力学进行了广泛的研究，但这些蛋白在不同功能状态下的潜在不同动力学行为仍然是难以捉摸的。本研究对四种进化上相关的蛋白质，包括A类β-内酰胺酶TEM-1和TOHO-1，两种PBP-A和DD-转肽酶，进行了分子动力学模拟和各种分析，以表征它们在不同功能状态下的动力学行为。青霉素G及其开环产物作为这四种目标蛋白的共同配体。整体结构的动态分析，青霉素G的活性位点，和三个催化重要的残基共同分享的所有四种蛋白质揭示了意外的交叉A类β-内酰胺酶和PBPs之间的相似性。这些发现揭示了这些蛋白质动力学行为之间的内在联系以及A类β-内酰胺酶和PBPs之间的功能和进化关系。
β-Lactamases are enzymes produced by bacteria to hydrolyze β-lactam-based antibiotics, and pose serious threat to public health through related antibiotic resistance. Class A β-lactamases are structurally and functionally related to penicillin-binding proteins (PBPs). Despite the extensive studies of the structures, catalytic mechanisms and dynamics of both β-lactamases and PBPs, the potentially different dynamical behaviors of these proteins in different functional states still remain elusive in general. In this study, four evolutionarily related proteins, including TEM-1 and TOHO-1 as class A β-lactamases, PBP-A and DD-transpeptidase as two PBPs, are subjected to molecular dynamics simulations and various analyses to characterize their dynamical behaviors in different functional states. Penicillin G and its ring opening product serve as common ligands for these four proteins of interest. The dynamic analyses of overall structures, the active sites with penicillin G, and three catalytically important residues commonly shared by all four proteins reveal unexpected cross similarities between Class A β-lactamases and PBPs. These findings shed light on both the hidden relations among dynamical behaviors of these proteins and the functional and evolutionary relations among class A β-lactamases and PBPs.
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