8hsy: Difference between revisions

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New page: '''Unreleased structure''' The entry 8hsy is ON HOLD Authors: Description: Category: Unreleased Structures
 
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'''Unreleased structure'''


The entry 8hsy is ON HOLD
==Acyl-ACP Synthetase structure==
<StructureSection load='8hsy' size='340' side='right'caption='[[8hsy]], [[Resolution|resolution]] 2.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8hsy]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Vibrio_harveyi Vibrio harveyi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HSY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.53&#8491;</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=8hsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hsy OCA], [https://pdbe.org/8hsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hsy RCSB], [https://www.ebi.ac.uk/pdbsum/8hsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hsy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q00IB3_VIBHA Q00IB3_VIBHA]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 A) and C10-AMP intermediate (2.19 A) in addition to its apo form (2.53 A). Apart from our measurements for C10-AMS' Ki value of around 0.6 muM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.


Authors:  
An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.,Huang H, Chang S, Cui T, Huang M, Qu J, Zhang H, Lu T, Zhang X, Zhou C, Feng Y PLoS Pathog. 2024 Jul 15;20(7):e1012376. doi: 10.1371/journal.ppat.1012376. , eCollection 2024 Jul. PMID:39008531<ref>PMID:39008531</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 8hsy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Vibrio harveyi]]
[[Category: Chang S]]
[[Category: Cui T]]
[[Category: Feng Y]]
[[Category: Huang H]]
[[Category: Wang C]]
[[Category: Xu Y]]
[[Category: Zhang H]]
[[Category: Zhang X]]
[[Category: Zhou C]]

Latest revision as of 09:28, 15 January 2025

Acyl-ACP Synthetase structureAcyl-ACP Synthetase structure

Structural highlights

8hsy is a 6 chain structure with sequence from Vibrio harveyi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.53Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q00IB3_VIBHA

Publication Abstract from PubMed

Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 A) and C10-AMP intermediate (2.19 A) in addition to its apo form (2.53 A). Apart from our measurements for C10-AMS' Ki value of around 0.6 muM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.,Huang H, Chang S, Cui T, Huang M, Qu J, Zhang H, Lu T, Zhang X, Zhou C, Feng Y PLoS Pathog. 2024 Jul 15;20(7):e1012376. doi: 10.1371/journal.ppat.1012376. , eCollection 2024 Jul. PMID:39008531[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. Huang H, Chang S, Cui T, Huang M, Qu J, Zhang H, Lu T, Zhang X, Zhou C, Feng Y. An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials. PLoS Pathog. 2024 Jul 15;20(7):e1012376. PMID:39008531 doi:10.1371/journal.ppat.1012376

8hsy, resolution 2.53Å

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