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Published October 6, 2015 | Version v1
Journal article Open

Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

Creators

  • 1. University of Chicago
  • 2. Brandeis University
  • 3. National Institute of Allergy and Infectious Diseases
  • 4. University of Minnesota
  • 5. University of Houston

Description

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.

Data availability

All relevant data are within the paper and its Supporting Information files. Coordinates and Structure factors are available in the Protein Data Bank (accession numbers 4ZQR, 4ZQP, 4ZQN, 4ZQO, 4ZQM).

Files

journal.pone.0138976.pdf

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Article
md5:10636ea441c4c72cbcd52e9a8d804b4f
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Additional details

Identifiers

DOI
10.1371/journal.pone.0138976
Other
oai:uchicago.tind.io:7524

Funding

National Institute of Allergy and Infectious Diseases
AI093459
National Institute of Allergy and Infectious Diseases
Intramural Research Program
U.S. Department of Energy
DE-AC02-06CH11357

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Genetics, Genomics, and Systems Biology
Center(s) or Institute(s)
Institute for Genomics and Systems Biology