Structure of Pseudomonas aeruginosa inosine 5-monophosphate dehydrogenase

Vincenzo A. Rao, Sharon M. Shepherd, Richard Owen, William N. Hunter

    Research output: Contribution to journalArticle

    13 Citations (Scopus)

    Abstract

    Inosine 5-monophosphate dehydrogenase (IMPDH) represents a potential antimicrobial drug target. The crystal structure of recombinant Pseudomonas aeruginosa IMPDH has been determined to a resolution of 2.25 angstrom. The structure is a homotetramer of subunits dominated by a (/)8-barrel fold, consistent with other known structures of IMPDH. Also in common with previous work, the cystathionine -synthase domains, residues 92204, are not present in the model owing to disorder. However, unlike the majority of available structures, clearly defined electron density exists for a loop that creates part of the active site. This loop, composed of residues 297315, links 8 and 9 and carries the catalytic Cys304. P. aeruginosa IMPDH shares a high level of sequence identity with bacterial and protozoan homologues, with residues involved in binding substrate and the NAD+ cofactor being conserved. Specific differences that have been proven to contribute to selectivity against the human enzyme in a study of Cryptosporidium parvum IMPDH are also conserved, highlighting the potential value of IMPDH as a drug target.

    Original languageEnglish
    Pages (from-to)243-247
    Number of pages5
    JournalActa Crystallographica F-Structural Biology and Crystallization Communications
    Volume69
    Issue number3
    DOIs
    Publication statusPublished - 2013

    Keywords

    • DESIGN
    • QUALITY
    • PROTEIN
    • MECHANISM
    • REFINEMENT
    • inosine 5-monophosphate dehydrogenase
    • 5'-MONOPHOSPHATE DEHYDROGENASE
    • CRYSTAL-STRUCTURE
    • RESOLUTION
    • INHIBITOR SELECTIVITY
    • antimicrobial drug targets
    • Pseudomonas aeruginosa
    • DRUG DISCOVERY

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