4ZQM

Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Mycobacterium tuberculosis in the complex with XMP and NAD

Summary for 4ZQM

• Entry DOI: 10.2210/pdb4zqm/pdb
• Related: 4ZQN 4ZQO 4ZQP 4ZQR
• Descriptor: Inosine-5'-monophosphate dehydrogenase,Inosine-5'-monophosphate dehydrogenase, XANTHOSINE-5'-MONOPHOSPHATE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: impdh, delta-cbs, mycobacterium tuberculosis, structural genomics, center for structural genomics of infectious diseases, csgid, oxidoreductase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 42671.26

Authors

Kim, Y.,Maltseva, N.,Makowska-Grzyska, M.,Gu, M.,Kavitha, M.,Hedstrom, L.,Anderson, W.F.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2015-05-10, release date: 2015-06-17, Last modification date: 2024-05-22)

Primary citation

Makowska-Grzyska, M.,Kim, Y.,Gorla, S.K.,Wei, Y.,Mandapati, K.,Zhang, M.,Maltseva, N.,Modi, G.,Boshoff, H.I.,Gu, M.,Aldrich, C.,Cuny, G.D.,Hedstrom, L.,Joachimiak, A.
Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds.
Plos One, 10:e0138976-e0138976, 2015

PubMed Abstract: Tuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5'-monophosphate into xanthosine 5'-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics.

PubMed: 26440283
DOI: 10.1371/journal.pone.0138976

Experimental method

X-RAY DIFFRACTION (1.602 Å)