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Allosteric cooperation in ß-lactam binding to a non-classical transpeptidase
bioRxiv - Biochemistry Pub Date : 2021-09-06 , DOI: 10.1101/2021.09.06.459080
Nazia Ahmad , Sangita Kachhap , Varsha Chauhan , Pallavi Juneja , Kunal Sharma , C. Korin Bullen , Tomasz Borowski , William R Bishai , Gyanu Lamichhane , Pankaj Kumar

Mycobacterium tuberculosis peptidoglycan (PG) is atypical as its synthesis involves a new enzyme class, L,D-transpeptidases. Prior studies of L,D-transpeptidases have identified only the catalytic site that binds to peptide moiety of the PG substrate or ß-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by ß-lactams. Here we report identification of an allosteric site at a distance of 21 Å from the catalytic site that binds the sugar moiety of PG substrates (hereafter referred to as the S-pocket). This site also binds a second ß-lactam molecule and influences binding at the catalytic site. We provide evidence that two ß-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-site and one covalently at the catalytic site. This dual ß-lactam binding phenomenon is previously unknown and is an observation that may offer novel approaches for the structure-based design of new ß-lactam antibiotics for M. tuberculosis.

中文翻译:

β-内酰胺与非经典转肽酶结合的变构合作

结核分枝杆菌肽聚糖 (PG) 是非典型的,因为它的合成涉及一种新的酶类 L,D-转肽酶。先前对 L,D-转肽酶的研究仅确定了与 PG 底物或 ß-内酰胺抗生素的肽部分结合的催化位点。这一见解被用来开发其活性和 ß-内酰胺抑制的机制。在这里,我们报告了距离催化位点 21 Å 处的变构位点的鉴定,该位点结合 PG 底物的糖部分(以下称为 S 袋)。该位点还结合第二个 ß-内酰胺分子并影响催化位点的结合。我们提供了两个 ß-内酰胺分子与该酶协同结合的证据,一个在 S 位非共价结合,一个在催化位点共价结合。结核分枝杆菌。
更新日期:2021-09-10
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