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==Crystal structure of Burkholderia pseudomallei D-alanine-D-alanine ligase in complex with AMP== | ==Crystal structure of Burkholderia pseudomallei D-alanine-D-alanine ligase in complex with AMP== | ||
<StructureSection load='5nrh' size='340' side='right' caption='[[5nrh]], [[Resolution|resolution]] 1.30Å' scene=''> | <StructureSection load='5nrh' size='340' side='right'caption='[[5nrh]], [[Resolution|resolution]] 1.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5nrh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NRH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NRH FirstGlance]. <br> | <table><tr><td colspan='2'>[[5nrh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pseudomallei"_whitmore_1913 "bacillus pseudomallei" whitmore 1913]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NRH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NRH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ddl, BURPS1106A_3548 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=28450 "Bacillus pseudomallei" Whitmore 1913])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/D-alanine--D-alanine_ligase D-alanine--D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.4 6.3.2.4] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/D-alanine--D-alanine_ligase D-alanine--D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.4 6.3.2.4] </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=5nrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nrh OCA], [http://pdbe.org/5nrh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nrh RCSB], [http://www.ebi.ac.uk/pdbsum/5nrh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nrh 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=5nrh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nrh OCA], [http://pdbe.org/5nrh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nrh RCSB], [http://www.ebi.ac.uk/pdbsum/5nrh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nrh ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/DDL_BURP0 DDL_BURP0]] Cell wall formation.[HAMAP-Rule:MF_00047] | [[http://www.uniprot.org/uniprot/DDL_BURP0 DDL_BURP0]] Cell wall formation.[HAMAP-Rule:MF_00047] | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Burkholderia pseudomallei is a serious, difficult to treat Gram-negative pathogen and an increase in the occurrence of drug-resistant strains has been detected. We have directed efforts to identify and to evaluate potential drug targets relevant to treatment of infection by B. pseudomallei. We have selected and characterised the essential enzyme d-alanine-d-alanine ligase (BpDdl), required for the ATP-assisted biosynthesis of a peptidoglycan precursor. A recombinant supply of protein supported high-resolution crystallographic and biophysical studies with ligands (AMP and AMP+d-Ala-d-Ala), and comparisons with orthologues enzymes suggest a ligand-induced conformational change occurring that might be relevant to the catalytic cycle. The detailed biochemical characterisation of the enzyme, development and optimisation of ligand binding assays supported the search for novel inhibitors by screening of selected compound libraries. In a similar manner to that observed previously in other studies, we note a paucity of hits that are worth follow-up and then in combination with a computational analysis of the active site, we conclude that this ligase represents a difficult target for drug discovery. Nevertheless, our reagents, protocols and data can underpin future efforts exploiting more diverse chemical libraries and structure-based approaches. | |||
Burkholderia pseudomallei d-alanine-d-alanine ligase; detailed characterisation and assessment of a potential antibiotic drug target.,Diaz-Saez L, Torrie LS, McElroy SP, Gray D, Hunter WN FEBS J. 2019 Jul 1. doi: 10.1111/febs.14976. PMID:31260169<ref>PMID:31260169</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5nrh" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[D-alanine-D-alanine ligase 3D structures|D-alanine-D-alanine ligase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus pseudomallei whitmore 1913]] | |||
[[Category: D-alanine--D-alanine ligase]] | [[Category: D-alanine--D-alanine ligase]] | ||
[[Category: Large Structures]] | |||
[[Category: Diaz-Saez, L]] | [[Category: Diaz-Saez, L]] | ||
[[Category: Hunter, W N]] | [[Category: Hunter, W N]] | ||
[[Category: Complex]] | [[Category: Complex]] | ||
[[Category: Ligase]] | [[Category: Ligase]] | ||
Revision as of 18:48, 28 August 2019
Crystal structure of Burkholderia pseudomallei D-alanine-D-alanine ligase in complex with AMPCrystal structure of Burkholderia pseudomallei D-alanine-D-alanine ligase in complex with AMP
Structural highlights
Function[DDL_BURP0] Cell wall formation.[HAMAP-Rule:MF_00047] Publication Abstract from PubMedBurkholderia pseudomallei is a serious, difficult to treat Gram-negative pathogen and an increase in the occurrence of drug-resistant strains has been detected. We have directed efforts to identify and to evaluate potential drug targets relevant to treatment of infection by B. pseudomallei. We have selected and characterised the essential enzyme d-alanine-d-alanine ligase (BpDdl), required for the ATP-assisted biosynthesis of a peptidoglycan precursor. A recombinant supply of protein supported high-resolution crystallographic and biophysical studies with ligands (AMP and AMP+d-Ala-d-Ala), and comparisons with orthologues enzymes suggest a ligand-induced conformational change occurring that might be relevant to the catalytic cycle. The detailed biochemical characterisation of the enzyme, development and optimisation of ligand binding assays supported the search for novel inhibitors by screening of selected compound libraries. In a similar manner to that observed previously in other studies, we note a paucity of hits that are worth follow-up and then in combination with a computational analysis of the active site, we conclude that this ligase represents a difficult target for drug discovery. Nevertheless, our reagents, protocols and data can underpin future efforts exploiting more diverse chemical libraries and structure-based approaches. Burkholderia pseudomallei d-alanine-d-alanine ligase; detailed characterisation and assessment of a potential antibiotic drug target.,Diaz-Saez L, Torrie LS, McElroy SP, Gray D, Hunter WN FEBS J. 2019 Jul 1. doi: 10.1111/febs.14976. PMID:31260169[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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