6r6a: Difference between revisions
New page: '''Unreleased structure''' The entry 6r6a is ON HOLD Authors: Krystufek, R., Sacha, P., Brynda, J., Konvalinka, J. Description: Major aspartyl peptidase 1 from C. neoformans [[Category... |
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==Major aspartyl peptidase 1 from C. neoformans== | |||
<StructureSection load='6r6a' size='340' side='right'caption='[[6r6a]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6r6a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Actinomyces Actinomyces] and [https://en.wikipedia.org/wiki/Cryptococcus_neoformans_var._grubii Cryptococcus neoformans var. grubii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R6A FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=IVA:ISOVALERIC+ACID'>IVA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STA:STATINE'>STA</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=6r6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6a OCA], [https://pdbe.org/6r6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r6a RCSB], [https://www.ebi.ac.uk/pdbsum/6r6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/J9VS02_CRYNH J9VS02_CRYNH] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted Cryptococcus neoformans protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors. | |||
Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery.,Krystufek R, Sacha P, Starkova J, Brynda J, Hradilek M, Tloust'ova E, Grzymska J, Rut W, Boucher MJ, Drag M, Majer P, Hajek M, Rezacova P, Madhani HD, Craik CS, Konvalinka J J Med Chem. 2021 May 27;64(10):6706-6719. doi: 10.1021/acs.jmedchem.0c02177. Epub, 2021 May 18. PMID:34006103<ref>PMID:34006103</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6r6a" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Brynda | <references/> | ||
[[Category: Konvalinka | __TOC__ | ||
</StructureSection> | |||
[[Category: Actinomyces]] | |||
[[Category: Cryptococcus neoformans var. grubii]] | |||
[[Category: Large Structures]] | |||
[[Category: Brynda J]] | |||
[[Category: Konvalinka J]] | |||
[[Category: Krystufek R]] | |||
[[Category: Sacha P]] | |||
Latest revision as of 15:16, 24 January 2024
Major aspartyl peptidase 1 from C. neoformansMajor aspartyl peptidase 1 from C. neoformans
Structural highlights
FunctionPublication Abstract from PubMedCryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted Cryptococcus neoformans protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors. Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery.,Krystufek R, Sacha P, Starkova J, Brynda J, Hradilek M, Tloust'ova E, Grzymska J, Rut W, Boucher MJ, Drag M, Majer P, Hajek M, Rezacova P, Madhani HD, Craik CS, Konvalinka J J Med Chem. 2021 May 27;64(10):6706-6719. doi: 10.1021/acs.jmedchem.0c02177. Epub, 2021 May 18. PMID:34006103[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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