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==Structure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid== | ==Structure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid== | ||
<StructureSection load='7oc0' size='340' side='right'caption='[[7oc0]]' scene=''> | <StructureSection load='7oc0' size='340' side='right'caption='[[7oc0]], [[Resolution|resolution]] 1.78Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OC0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OC0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7oc0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OC0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OC0 FirstGlance]. <br> | ||
</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=7oc0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oc0 OCA], [https://pdbe.org/7oc0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oc0 RCSB], [https://www.ebi.ac.uk/pdbsum/7oc0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oc0 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=V7W:(2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic+acid'>V7W</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fabF1, PA2965 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 PSEAE])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-ketoacyl-[acyl-carrier-protein]_synthase_II Beta-ketoacyl-[acyl-carrier-protein] synthase II], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.179 2.3.1.179] </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=7oc0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oc0 OCA], [https://pdbe.org/7oc0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oc0 RCSB], [https://www.ebi.ac.uk/pdbsum/7oc0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oc0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/G3XDA2_PSEAE G3XDA2_PSEAE]] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity).[PIRNR:PIRNR000447] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF. | |||
An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.,Espeland LO, Georgiou C, Klein R, Bhukya H, Haug BE, Underhaug J, Mainkar PS, Brenk R ChemMedChem. 2021 Jun 29. doi: 10.1002/cmdc.202100302. PMID:34189850<ref>PMID:34189850</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7oc0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Brenk R]] | [[Category: Pseae]] | ||
[[Category: Espeland | [[Category: Brenk, R]] | ||
[[Category: Georgiou C]] | [[Category: Espeland, L O]] | ||
[[Category: Klein R]] | [[Category: Georgiou, C]] | ||
[[Category: Klein, R]] | |||
[[Category: Antibiotic]] | |||
[[Category: Fatty acid biosynthesis pathway]] | |||
[[Category: Inhibitor]] | |||
Revision as of 10:03, 22 September 2021
Structure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acidStructure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid
Structural highlights
Function[G3XDA2_PSEAE] Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity).[PIRNR:PIRNR000447] Publication Abstract from PubMedFabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF. An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.,Espeland LO, Georgiou C, Klein R, Bhukya H, Haug BE, Underhaug J, Mainkar PS, Brenk R ChemMedChem. 2021 Jun 29. doi: 10.1002/cmdc.202100302. PMID:34189850[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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