4af0

Crystal structure of cryptococcal inosine monophosphate dehydrogenase

spinqualitylabelsall models 4af0, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4af0 is a 2 chain structure with sequence from Crynh. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: IMP, MOA, SO4 Activity: IMP dehydrogenase, with EC number 1.1.1.205 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [E3P6S0_CRYNE] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_03156] Publication Abstract from PubMed We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the Cryptococcus species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of C. gattii that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from Cryptococcus, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating de novo GTP biosynthesis as an antifungal target in Cryptococcus. De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans.,Morrow CA, Valkov E, Stamp A, Chow EW, Lee IR, Wronski A, Williams SJ, Hill JM, Djordjevic JT, Kappler U, Kobe B, Fraser JA PLoS Pathog. 2012 Oct;8(10):e1002957. doi: 10.1371/journal.ppat.1002957. Epub, 2012 Oct 11. PMID:23071437 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Inosine monophosphate dehydrogenase

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