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| | ==n-Alkylboronic Acid Inhibitors Reveal Determinants of Ligand Specificity in the Quorum-Quenching and Siderophore Biosynthetic Enzyme PvdQ== | | ==n-Alkylboronic Acid Inhibitors Reveal Determinants of Ligand Specificity in the Quorum-Quenching and Siderophore Biosynthetic Enzyme PvdQ== |
| - | <StructureSection load='4wku' size='340' side='right' caption='[[4wku]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4wku' size='340' side='right'caption='[[4wku]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wku]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WKU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WKU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wku]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WKU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3QJ:HEXYL(TRIHYDROXY)BORATE(1-)'>3QJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wks|4wks]], [[4wkt|4wkt]], [[4wkv|4wkv]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QJ:HEXYL(TRIHYDROXY)BORATE(1-)'>3QJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4wku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wku OCA], [https://pdbe.org/4wku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wku RCSB], [https://www.ebi.ac.uk/pdbsum/4wku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wku ProSAT]</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=4wku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wku OCA], [http://pdbe.org/4wku PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wku RCSB], [http://www.ebi.ac.uk/pdbsum/4wku PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wku ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PVDQ_PSEAE PVDQ_PSEAE]] Catalyzes the deacylation of acyl-homoserine lactone (AHL or acyl-HSL), releasing homoserine lactone (HSL) and the corresponding fatty acid. Possesses a specificity for the degradation of long-chain acyl-HSLs (side chains of 11 to 14 carbons in length). Degrades 3-oxo-C12-HSL, one of the two main AHL signal molecules of P.aeruginosa, and thereby functions as a quorum quencher, inhibiting the las quorum-sensing system. Therefore, may enable P.aeruginosa to modulate its own quorum-sensing-dependent pathogenic potential. Also appears to be required for pyoverdin biosynthesis.<ref>PMID:16495538</ref> <ref>PMID:14532048</ref> <ref>PMID:12686626</ref> | + | [https://www.uniprot.org/uniprot/PVDQ_PSEAE PVDQ_PSEAE] Catalyzes the deacylation of acyl-homoserine lactone (AHL or acyl-HSL), releasing homoserine lactone (HSL) and the corresponding fatty acid. Possesses a specificity for the degradation of long-chain acyl-HSLs (side chains of 11 to 14 carbons in length). Degrades 3-oxo-C12-HSL, one of the two main AHL signal molecules of P.aeruginosa, and thereby functions as a quorum quencher, inhibiting the las quorum-sensing system. Therefore, may enable P.aeruginosa to modulate its own quorum-sensing-dependent pathogenic potential. Also appears to be required for pyoverdin biosynthesis.<ref>PMID:16495538</ref> <ref>PMID:14532048</ref> <ref>PMID:12686626</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acyl-homoserine-lactone acylase]] | + | [[Category: Large Structures]] |
| - | [[Category: Clevenger, K D]] | + | [[Category: Pseudomonas aeruginosa PAO1]] |
| - | [[Category: Fast, W]] | + | [[Category: Clevenger KD]] |
| - | [[Category: Liu, D]] | + | [[Category: Fast W]] |
| - | [[Category: Wu, R]] | + | [[Category: Liu D]] |
| - | [[Category: N-alkylboronic acid inhibitors of pvdq]]
| + | [[Category: Wu R]] |
| Structural highlights
Function
PVDQ_PSEAE Catalyzes the deacylation of acyl-homoserine lactone (AHL or acyl-HSL), releasing homoserine lactone (HSL) and the corresponding fatty acid. Possesses a specificity for the degradation of long-chain acyl-HSLs (side chains of 11 to 14 carbons in length). Degrades 3-oxo-C12-HSL, one of the two main AHL signal molecules of P.aeruginosa, and thereby functions as a quorum quencher, inhibiting the las quorum-sensing system. Therefore, may enable P.aeruginosa to modulate its own quorum-sensing-dependent pathogenic potential. Also appears to be required for pyoverdin biosynthesis.[1] [2] [3]
Publication Abstract from PubMed
The enzyme PvdQ (E.C. 3.5.1.97) from Pseudomonas aeruginosa is an N-terminal nucleophile hydrolase that catalyzes the removal of an N-myristyl substituent from a biosynthetic precursor of the iron-chelating siderophore pyoverdine. Inhibitors of pyoverdine biosynthesis are potential antibiotics since iron is essential for growth and scarce in most infections. PvdQ also catalyzes hydrolytic amide bond cleavage of selected N-acyl-l-homoserine lactone quorum-sensing signals used by some Gram-negative pathogens to coordinate the transcription of virulence factors. The resulting quorum-quenching activity of PvdQ has potential applications in antivirulence therapies. To inform both inhibitor design and enzyme engineering efforts, a series of n-alkylboronic acid inhibitors of PvdQ was characterized to reveal determinants of ligand selectivity. A simple homologation series results in compounds with Ki values that span from 4.7 mM to 190 pM, with a dependence of DeltaGbind values on chain length of -1.0 kcal/mol/CH2. X-ray crystal structures are determined for the PvdQ complexes with 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octylboronic acids at 1.6, 1.8, 2.0, and 2.1 A resolution, respectively. The 1-hexyl- and 1-octylboronic acids form tetrahedral adducts with the active-site N-terminal Ser217 in the beta-subunit of PvdQ, and the n-alkyl substituents are bound in the acyl-group binding site. The 1-ethyl- and 1-butylboronic acids also form adducts with Ser217 but instead form trigonal planar adducts and extend their n-alkyl substituents into an alternative binding site. These results are interpreted to propose a ligand discrimination model for PvdQ that informs the development of PvdQ-related tools and therapeutics.
n-Alkylboronic Acid Inhibitors Reveal Determinants of Ligand Specificity in the Quorum-Quenching and Siderophore Biosynthetic Enzyme PvdQ.,Clevenger KD, Wu R, Liu D, Fast W Biochemistry. 2014 Oct 28;53(42):6679-86. doi: 10.1021/bi501086s. Epub 2014 Oct, 17. PMID:25290020[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sio CF, Otten LG, Cool RH, Diggle SP, Braun PG, Bos R, Daykin M, Camara M, Williams P, Quax WJ. Quorum quenching by an N-acyl-homoserine lactone acylase from Pseudomonas aeruginosa PAO1. Infect Immun. 2006 Mar;74(3):1673-82. PMID:16495538 doi:74/3/1673
- ↑ Huang JJ, Han JI, Zhang LH, Leadbetter JR. Utilization of acyl-homoserine lactone quorum signals for growth by a soil pseudomonad and Pseudomonas aeruginosa PAO1. Appl Environ Microbiol. 2003 Oct;69(10):5941-9. PMID:14532048
- ↑ Lamont IL, Martin LW. Identification and characterization of novel pyoverdine synthesis genes in Pseudomonas aeruginosa. Microbiology. 2003 Apr;149(Pt 4):833-42. PMID:12686626
- ↑ Clevenger KD, Wu R, Liu D, Fast W. n-Alkylboronic Acid Inhibitors Reveal Determinants of Ligand Specificity in the Quorum-Quenching and Siderophore Biosynthetic Enzyme PvdQ. Biochemistry. 2014 Oct 28;53(42):6679-86. doi: 10.1021/bi501086s. Epub 2014 Oct, 17. PMID:25290020 doi:http://dx.doi.org/10.1021/bi501086s
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