A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.
A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.
复制标题
DOI：
10.1074/jbc.m114.619767
复制
发表时间：
2015-02-27
期刊：
影响因子：
--
通讯作者：
Joachimiak A
中科院分区：
文献类型：
--
作者：
Makowska-Grzyska M;Kim Y;Maltseva N;Osipiuk J;Gu M;Zhang M;Mandapati K;Gollapalli DR;Gorla SK;Hedstrom L;Joachimiak A
Background: IMP dehydrogenase (IMPDH) is an important drug target because of its role in de novo purine nucleotide biosynthesis. Results: First substrate/cofactor- and substrate/inhibitor-bound complexes of bacterial IMPDHs are determined. Conclusion: A new distinct binding mode of the cofactor adenosine moiety is revealed. Significance: This work offers new insights for the design of more potent and selective inhibitors and the evolution of the active site. The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5′-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD+, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD+ and XMP/NAD+. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD+-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD+-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. These findings offer a potential strategy for further ligand optimization.
