4af0: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='4af0' size='340' side='right'caption='[[4af0]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='4af0' size='340' side='right'caption='[[4af0]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4af0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4af0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptococcus_neoformans_var._grubii_H99 Cryptococcus neoformans var. grubii H99]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AF0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AF0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=MOA:MYCOPHENOLIC+ACID'>MOA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=MOA:MYCOPHENOLIC+ACID'>MOA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4af0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4af0 OCA], [https://pdbe.org/4af0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4af0 RCSB], [https://www.ebi.ac.uk/pdbsum/4af0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4af0 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4af0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4af0 OCA], [https://pdbe.org/4af0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4af0 RCSB], [https://www.ebi.ac.uk/pdbsum/4af0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4af0 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/E3P6S0_CRYNE 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] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 26: | Line 26: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Cryptococcus neoformans var. grubii H99]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Fraser | [[Category: Fraser JA]] | ||
[[Category: Kobe | [[Category: Kobe B]] | ||
[[Category: Morrow | [[Category: Morrow CA]] | ||
[[Category: Stamp | [[Category: Stamp A]] | ||
[[Category: Valkov | [[Category: Valkov E]] | ||
Latest revision as of 14:25, 20 December 2023
Crystal structure of cryptococcal inosine monophosphate dehydrogenaseCrystal structure of cryptococcal inosine monophosphate dehydrogenase
Structural highlights
FunctionE3P6S0_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 PubMedWe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||