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PDBsum entry 4zqn
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4zqn
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References listed in PDB file
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Key reference
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Title
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Mycobacterium tuberculosis impdh in complexes with substrates, Products and antitubercular compounds.
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Authors
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M.Makowska-Grzyska,
Y.Kim,
S.K.Gorla,
Y.Wei,
K.Mandapati,
M.Zhang,
N.Maltseva,
G.Modi,
H.I.Boshoff,
M.Gu,
C.Aldrich,
G.D.Cuny,
L.Hedstrom,
A.Joachimiak.
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Ref.
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Plos One, 2015,
10,
e0138976.
[DOI no: ]
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PubMed id
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Abstract
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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.
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