Graduate School of Genome Science and Technology , The University of Tennessee and Oak Ridge National Laboratory , 1414 West Cumberland Avenue , Knoxville , Tennessee 37996 , United States.
Neutron Sciences Directorate , Oak Ridge National Laboratory , Oak Ridge , Tennessee 37831 , United States.
J Med Chem. 2018 Nov 21;61(22):10218-10227. doi: 10.1021/acs.jmedchem.8b01393. Epub 2018 Oct 31.
Aminoglycoside antibiotics are a large family of antibiotics that can be divided into two distinct classes on the basis of the substitution pattern of the central deoxystreptamine ring. Although aminoglycosides are chemically, structurally, and topologically diverse, some aminoglycoside-modifying enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides from the two main classes, the kanamycin- and neomycin-based antibiotics. Here, we present the crystal structure of a promiscuous AGME, aminoglycoside- N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A (CoASH) complexes, and in the ternary neomycin-CoASH complex. These data provide a structural framework for interpretation of the thermodynamics of enzyme-ligand interactions and the role of solvent in the recognition of ligands. In combination with the recent structure of an AGME that does not have broad substrate specificity, these structures allow for the direct determination of how antibiotic promiscuity is encoded in some AGMEs.
氨基糖苷类抗生素是一大类抗生素，根据中心脱氧链霉胺环的取代模式可以分为两个不同的类别。尽管氨基糖苷类在化学、结构和拓扑上具有多样性，但一些氨基糖苷修饰酶（AGMEs）能够使两种主要类别中的多达 15 种氨基糖苷失活，即卡那霉素和新霉素类抗生素。在这里，我们展示了一种混杂的 AGME，氨基糖苷-N3-乙酰基转移酶-IIIb（AAC-IIIb）的晶体结构，分别为无配体形式、二元药物（西索米星、新霉素和巴龙霉素）和辅酶 A（CoASH）复合物，以及三元新霉素-CoASH 复合物形式。这些数据为解释酶-配体相互作用的热力学和溶剂在配体识别中的作用提供了结构框架。结合最近没有广泛底物特异性的 AGME 结构，这些结构可以直接确定某些 AGME 中抗生素混杂性是如何编码的。
