4bnk: Difference between revisions
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==Crystal structure of S. aureus FabI in complex with NADP and 5-fluoro- 2-phenoxyphenol== | ==Crystal structure of S. aureus FabI in complex with NADP and 5-fluoro- 2-phenoxyphenol== | ||
<StructureSection load='4bnk' size='340' side='right' caption='[[4bnk]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='4bnk' size='340' side='right'caption='[[4bnk]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bnk]] is a 8 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4bnk]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_N315 Staphylococcus aureus subsp. aureus N315]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BNK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BNK FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FPL:5-FLUORO-2-PHENOXYPHENOL'>FPL</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FPL:5-FLUORO-2-PHENOXYPHENOL'>FPL</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=4bnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bnk OCA], [https://pdbe.org/4bnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bnk RCSB], [https://www.ebi.ac.uk/pdbsum/4bnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bnk ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0H3JLH9_STAAN A0A0H3JLH9_STAAN] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4bnk" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Enoyl-Acyl-Carrier Protein Reductase|Enoyl-Acyl-Carrier Protein Reductase]] | *[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Staphylococcus aureus subsp. aureus | [[Category: Large Structures]] | ||
[[Category: Bommineni | [[Category: Staphylococcus aureus subsp. aureus N315]] | ||
[[Category: Chang | [[Category: Bommineni GR]] | ||
[[Category: Kisker | [[Category: Chang A]] | ||
[[Category: Schiebel | [[Category: Kisker C]] | ||
[[Category: Tonge | [[Category: Schiebel J]] | ||
[[Category: Tonge PJ]] | |||
Latest revision as of 14:55, 20 December 2023
Crystal structure of S. aureus FabI in complex with NADP and 5-fluoro- 2-phenoxyphenolCrystal structure of S. aureus FabI in complex with NADP and 5-fluoro- 2-phenoxyphenol
Structural highlights
FunctionPublication Abstract from PubMedDrug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex.,Chang A, Schiebel J, Yu W, Bommineni GR, Pan P, Baxter MV, Khanna A, Sotriffer CA, Kisker CF, Tonge PJ Biochemistry. 2013 May 22. PMID:23697754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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