4MZ1

Crystal Structure of the Inosine 5'-monophosphate Dehydrogenase, with a Internal Deletion of CBS Domain from Campylobacter jejuni complexed with inhibitor compound P12

Summary for 4MZ1

• Entry DOI: 10.2210/pdb4mz1/pdb
• Descriptor: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 1-(4-bromophenyl)-3-{2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl}urea, ... (8 entities in total)
• Functional Keywords: structural genomics, niaid, national institute of allergy and infectious diseases, center for structural genomics of infectious diseases, csgid, tim barrel, alpha-beta structure, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Campylobacter jejuni subsp. jejuni; More
• Total number of polymer chains: 3
• Total formula weight: 126515.48

Authors

Kim, Y.,Makowska-Grzyska, M.,Gu, M.,Anderson, W.F.,Joachimiak, A.,CSGID,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2013-09-28, release date: 2014-01-01, Last modification date: 2026-03-25)

Primary citation

Makowska-Grzyska, M.,Kim, Y.,Maltseva, N.,Osipiuk, J.,Gu, M.,Zhang, M.,Mandapati, K.,Gollapalli, D.R.,Gorla, S.K.,Hedstrom, L.,Joachimiak, A.
A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.
J.Biol.Chem., 290:5893-5911, 2015

PubMed Abstract: 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.

PubMed: 25572472
DOI: 10.1074/jbc.M114.619767

Experimental method

X-RAY DIFFRACTION (2.3991 Å)