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< | ==Crystal structure of the Y248A mutant of C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus in complex with zaragozic acid A== | ||
<StructureSection load='3vje' size='340' side='right'caption='[[3vje]], [[Resolution|resolution]] 2.12Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3vje]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VJE 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]] 2.12Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZGA:ZARAGOZIC+ACID+A'>ZGA</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=3vje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vje OCA], [https://pdbe.org/3vje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vje RCSB], [https://www.ebi.ac.uk/pdbsum/3vje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vje ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CRTM_STAAU CRTM_STAAU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors. | |||
Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.,Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH J Biol Chem. 2012 May 25;287(22):18750-7. Epub 2012 Apr 3. PMID:22474324<ref>PMID:22474324</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3vje" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Squalene synthase|Squalene synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[ | |||
== | |||
< | |||
[[Category: Staphylococcus aureus]] | [[Category: Staphylococcus aureus]] | ||
[[Category: Chang | [[Category: Chang WJ]] | ||
[[Category: Jeng | [[Category: Jeng WY]] | ||
[[Category: Liu | [[Category: Liu CI]] | ||
[[Category: Wang | [[Category: Wang AHJ]] | ||
Latest revision as of 15:23, 8 November 2023
Crystal structure of the Y248A mutant of C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus in complex with zaragozic acid ACrystal structure of the Y248A mutant of C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus in complex with zaragozic acid A
Structural highlights
FunctionPublication Abstract from PubMedZaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.,Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH J Biol Chem. 2012 May 25;287(22):18750-7. Epub 2012 Apr 3. PMID:22474324[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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