Institut Pasteur, Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, CNRS UMR3523, 28 rue du Dr Roux, F-75015, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, F-75205, Paris, France.
Institut Pasteur, Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, CNRS UMR3523, 28 rue du Dr Roux, F-75015, Paris, France.
Eur J Med Chem. 2019 Apr 1;167:124-132. doi: 10.1016/j.ejmech.2019.01.064. Epub 2019 Feb 2.
Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.
肌苷-5'-单磷酸脱氢酶（IMPDH）是许多细菌病原体中必需的酶，被认为是开发新型抗菌药物的潜在药物靶点。我们最近的工作揭示了两个结构域之一（即 Bateman 结构域）在调节细菌 IMPDH 的四级结构和酶活性方面的关键作用。因此，我们筛选了化学文库，以寻找靶向 Bateman 结构域的化合物，并鉴定了一类新型的细菌 IMPDH 的别构抑制剂。这些抑制剂被证明可以拮抗天然正向效应物 MgATP 的激活，并使酶处于apo 构象（对 IMP 的亲和力低）。我们的结构研究证明了 Bateman 结构域具有适应完全不相关的化学支架的多功能性，为开发别构抑制剂铺平了道路，这是迄今为止很少探索的途径。
