4m1j: Difference between revisions
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==Crystal structure of Pseudomonas aeruginosa PvdQ in complex with a transition state analogue== | |||
<StructureSection load='4m1j' size='340' side='right' caption='[[4m1j]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4m1j]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M1J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M1J FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B0S:TRIDECYLBORONIC+ACID'>B0S</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PA2385, pvdQ, qsc112 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 Pseudomonas aeruginosa]), pvdQ, qsc112, PA2385 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 Pseudomonas aeruginosa])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acyl-homoserine-lactone_acylase Acyl-homoserine-lactone acylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.97 3.5.1.97] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4m1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m1j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4m1j RCSB], [http://www.ebi.ac.uk/pdbsum/4m1j PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Pseudomonas aeruginosa enzyme PvdQ can process different substrates involved in quorum-sensing or in siderophore biosynthesis. Substrate selectivity was evaluated using steady-state kinetic constants for hydrolysis of N-acyl-homoserine lactones (HSLs) and p-nitrophenyl fatty acid esters. PvdQ prefers substrates with alkyl chains between 12 and 14 carbons long that do not bear a 3-oxo substitution and is revealed here to have a relatively high specificity constant for selected N-acyl-HSLs (kcat/KM = 105 to 106 M-1 s-1). However, endogenous P. aeruginosa N-acyl-HSLs are >/=100-fold disfavored, supporting the conclusion that PvdQ was not primarily evolved to regulate endogenous quorum-sensing. PvdQ plays an essential biosynthetic role for the siderophore pyoverdine, on which P. aeruginosa depends for growth in iron-limited environments. A series of alkylboronate inhibitors was found to be reversible, competitive, and extremely potent (Ki >/= 190 pM). A 1.8 A X-ray structure shows that 1-tridecylboronic acid forms a monocovalent bond with the N-terminal beta-chain Ser residue in the PvdQ heterodimer, mimicking a reaction transition state. This boronic acid inhibits growth of P. aeruginosa in iron-limited media, reproducing the phenotype of a genetic pvdQ disruption, although co-administration of an efflux pump inhibitor is required to maintain growth inhibition. These findings support the strategy of designing boron-based inhibitors of siderophore biosynthetic enzymes to control P. aeruginosa infections. | |||
Rational Design of a Transition State Analogue with Picomolar Affinity for Pseudomonas aeruginosa PvdQ, a Siderophore Biosynthetic Enzyme.,Clevenger KD, Wu R, Er JA, Liu D, Fast W ACS Chem Biol. 2013 Aug 6. PMID:23883096<ref>PMID:23883096</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Acyl-homoserine-lactone acylase]] | [[Category: Acyl-homoserine-lactone acylase]] | ||
[[Category: Pseudomonas aeruginosa]] | [[Category: Pseudomonas aeruginosa]] | ||
[[Category: Clevenger, K | [[Category: Clevenger, K]] | ||
[[Category: Er, J | [[Category: Er, J]] | ||
[[Category: Fast, W L | [[Category: Fast, W L]] | ||
[[Category: Liu, D | [[Category: Liu, D]] | ||
[[Category: Wu, R | [[Category: Wu, R]] | ||
[[Category: Acylase]] | [[Category: Acylase]] | ||
[[Category: Boronic acid]] | [[Category: Boronic acid]] | ||
Revision as of 18:22, 21 December 2014
Crystal structure of Pseudomonas aeruginosa PvdQ in complex with a transition state analogueCrystal structure of Pseudomonas aeruginosa PvdQ in complex with a transition state analogue
Structural highlights
Publication Abstract from PubMedThe Pseudomonas aeruginosa enzyme PvdQ can process different substrates involved in quorum-sensing or in siderophore biosynthesis. Substrate selectivity was evaluated using steady-state kinetic constants for hydrolysis of N-acyl-homoserine lactones (HSLs) and p-nitrophenyl fatty acid esters. PvdQ prefers substrates with alkyl chains between 12 and 14 carbons long that do not bear a 3-oxo substitution and is revealed here to have a relatively high specificity constant for selected N-acyl-HSLs (kcat/KM = 105 to 106 M-1 s-1). However, endogenous P. aeruginosa N-acyl-HSLs are >/=100-fold disfavored, supporting the conclusion that PvdQ was not primarily evolved to regulate endogenous quorum-sensing. PvdQ plays an essential biosynthetic role for the siderophore pyoverdine, on which P. aeruginosa depends for growth in iron-limited environments. A series of alkylboronate inhibitors was found to be reversible, competitive, and extremely potent (Ki >/= 190 pM). A 1.8 A X-ray structure shows that 1-tridecylboronic acid forms a monocovalent bond with the N-terminal beta-chain Ser residue in the PvdQ heterodimer, mimicking a reaction transition state. This boronic acid inhibits growth of P. aeruginosa in iron-limited media, reproducing the phenotype of a genetic pvdQ disruption, although co-administration of an efflux pump inhibitor is required to maintain growth inhibition. These findings support the strategy of designing boron-based inhibitors of siderophore biosynthetic enzymes to control P. aeruginosa infections. Rational Design of a Transition State Analogue with Picomolar Affinity for Pseudomonas aeruginosa PvdQ, a Siderophore Biosynthetic Enzyme.,Clevenger KD, Wu R, Er JA, Liu D, Fast W ACS Chem Biol. 2013 Aug 6. PMID:23883096[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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