Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases
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DOI：
10.1016/j.chembiol.2009.04.010
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发表时间：
2009-05-29
影响因子：
--
通讯作者：
Mangani, Stefano
中科院分区：
文献类型：
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作者：
Docquier, Jean-Denis;Calderone, Vito;Mangani, Stefano
碳青霉烯水解D类β-内酰胺酶（CHDL）是在重要的革兰氏阴性病原体（主要是鲍曼不动杆菌和肠杆菌科）中发现的酶，可赋予对β-内酰胺抗生素（尤其是碳青霉烯类）的耐药性。OXA-48碳青霉烯酶的晶体结构在pH 7.5和1.9埃的分辨率下测定。令人惊讶的是，与OXA-24（已知晶体结构的唯一其他CHDL）相比，OXA-48的结构与OXA-10（一种缺乏碳青霉烯酶活性的酶）相似，表明这些化合物的水解可能取决于活性位点区域的细微变化。此外，OXA-48的活性位点凹槽在形状、尺寸和电荷分布上不同于OXA-24的活性位点凹槽。分子动力学指出了位于或接近β 5-β 6环的残基的功能相关性，并使我们能够提出OXA-48水解碳青霉烯的机制。
Carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are enzymes found in important Gram-negative pathogens (mainly Acinetobacter baumannii and Enterobacteriaceae) that confer resistance to beta-lactam antibiotics, and notably carbapenems. The crystal structure of the OXA-48 carbapenemase was determined at pH 7.5 and at a resolution of 1.9 angstrom. Surprisingly, and by contrast with OXA-24, the only other CHDL of known crystal structure, the structure of OXA-48 was similar to OXA-10, an enzyme devoid of carbapenemase activity, indicating that the hydrolysis of these compounds could depend on subtle changes in the active site region. Moreover, the active site groove of OXA-48 was different from that of OXA-24 in shape, dimensions, and charge distribution. Molecular dynamics pointed to the functional relevance of residues located in or close to the beta 5-beta 6 loop and allowed us to propose a mechanism for carbapenem hydrolysis by OXA-48.