7mgq
From Proteopedia
(Difference between revisions)
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==AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans== | ==AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans== | ||
| - | <StructureSection load='7mgq' size='340' side='right'caption='[[7mgq]]' scene=''> | + | <StructureSection load='7mgq' size='340' side='right'caption='[[7mgq]], [[Resolution|resolution]] 2.67Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MGQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MGQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7mgq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptococcus_neoformans Cryptococcus neoformans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MGQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MGQ FirstGlance]. <br> |
| - | </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=7mgq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mgq OCA], [https://pdbe.org/7mgq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mgq RCSB], [https://www.ebi.ac.uk/pdbsum/7mgq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mgq ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7mgq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mgq OCA], [https://pdbe.org/7mgq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mgq RCSB], [https://www.ebi.ac.uk/pdbsum/7mgq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mgq ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/A0A225ZZG7_CRYNV A0A225ZZG7_CRYNV] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The fungal pathogen Cryptococcus neoformans is a leading cause of meningoencephalitis in the immunocompromised. As current antifungal treatments are toxic to the host, costly, limited in their efficacy, and associated with drug resistance, there is an urgent need to identify vulnerabilities in fungal physiology to accelerate antifungal discovery efforts. Rational drug design was pioneered in de novo purine biosynthesis as the end products of the pathway, ATP and GTP, are essential for replication, transcription, and energy metabolism, and the same rationale applies when considering the pathway as an antifungal target. Here, we describe the identification and characterization of C. neoformans 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/5'-inosine monophosphate cyclohydrolase (ATIC), a bifunctional enzyme that catalyzes the final two enzymatic steps in the formation of the first purine base inosine monophosphate. We demonstrate that mutants lacking the ATIC-encoding ADE16 gene are adenine and histidine auxotrophs that are unable to establish an infection in a murine model of virulence. In addition, our assays employing recombinantly expressed and purified C. neoformans ATIC enzyme revealed Km values for its substrates AICAR and 5-formyl-AICAR are 8-fold and 20-fold higher, respectively, than in the human ortholog. Subsequently, we performed crystallographic studies that enabled the determination of the first fungal ATIC protein structure, revealing a key serine-to-tyrosine substitution in the active site, which has the potential to assist the design of fungus-specific inhibitors. Overall, our results validate ATIC as a promising antifungal drug target. | ||
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| + | AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans.,Wizrah MSI, Chua SMH, Luo Z, Manik MK, Pan M, Whyte JML, Robertson AAB, Kappler U, Kobe B, Fraser JA J Biol Chem. 2022 Oct;298(10):102453. doi: 10.1016/j.jbc.2022.102453. Epub 2022, Sep 5. PMID:36063996<ref>PMID:36063996</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7mgq" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Cryptococcus neoformans]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chua SMH]] | [[Category: Chua SMH]] | ||
Revision as of 07:32, 3 November 2022
AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans
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Categories: Cryptococcus neoformans | Large Structures | Chua SMH | Fraser JA | Kappler U | Kobe B | Luo Z | Manik MK | Pan M | Robertson AB | Whyte JM | Wizrah MS
