ArticleThe Journal of biological chemistry2015
A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Statistical Thermodynamics of the Protein Ensemble: Mediating Function and Evolution.Annual review of biophysics · 2025Review
- Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding.ACS infectious diseases · 2025Article
- Vitamin B6 inhibits activity ofJournal of enzyme inhibition and medicinal chemistry · 2024Article
- Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition inJournal of bacteriology · 2024Article
- Deciphering the allosteric regulation of mycobacterial inosine-5'-monophosphate dehydrogenase.Nature communications · 2024Article
- The mycobacterial guaB1 gene encodes a guanosine 5'-monophosphate reductase with a cystathionine-β-synthase domain.The FEBS journal · 2022Article
- The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target forACS infectious diseases · 2021Article
- Discovery of Novel GMPS Inhibitors ofBiology · 2021Article
- A probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase.Journal of molecular modeling · 2021Article
- Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors.Bioorganic & medicinal chemistry letters · 2020Article
- Evaluation of Bronopol and Disulfiram as PotentialMolecules (Basel, Switzerland) · 2020Article
- Horizontal transfer of a pathway for coumarate catabolism unexpectedly inhibits purine nucleotide biosynthesis.Molecular microbiology · 2019Article
- Inhibitors of inosine 5'-monophosphate dehydrogenase as emerging new generation antimicrobial agents.MedChemComm · 2019Review
- Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase.Chemical research in toxicology · 2019Article
- Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure-Activity As Potential Antituberculosis Agents.Journal of medicinal chemistry · 2018Article
- Benzoxazoles, Phthalazinones, and Arylurea-Based Compounds with IMP Dehydrogenase-Independent Antibacterial Activity against Francisella tularensis.Antimicrobial agents and chemotherapy · 2017Article
- A nucleotide-controlled conformational switch modulates the activity of eukaryotic IMP dehydrogenases.Scientific reports · 2017Article
- The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis.ACS infectious diseases · 2017Article
- Inhibition of Inosine-5'-monophosphate Dehydrogenase from Bacillus anthracis: Mechanism Revealed by Pre-Steady-State Kinetics.Biochemistry · 2016Article
- The cystathionine-β-synthase domains on the guanosine 5''-monophosphate reductase and inosine 5'-monophosphate dehydrogenase enzymes from Leishmania regulate enzymatic activity in response to guanylate and adenylate nucleotide levels.Molecular microbiology · 2016Article
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Authors and funding
11 authors.
Funding
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.
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