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| | ==Crystal structure of S. aureus FabI in complex with NADP and 2- phenoxy-5-propylphenol== | | ==Crystal structure of S. aureus FabI in complex with NADP and 2- phenoxy-5-propylphenol== |
| - | <StructureSection load='4bnf' size='340' side='right' caption='[[4bnf]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='4bnf' size='340' side='right'caption='[[4bnf]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bnf]] is a 8 chain structure with sequence from [http://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=4BNF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BNF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bnf]] 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=4BNF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BNF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PV4:2-PHENOXY-5-PROPYL-PHENOL'>PV4</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]] 2.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bng|4bng]], [[4bnh|4bnh]], [[4bni|4bni]], [[4bnj|4bnj]], [[4bnk|4bnk]], [[4bnl|4bnl]], [[4bnm|4bnm]], [[4bnn|4bnn]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PV4:2-PHENOXY-5-PROPYL-PHENOL'>PV4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADPH,_B-specific) Enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.10 1.3.1.10] </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=4bnf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bnf OCA], [https://pdbe.org/4bnf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bnf RCSB], [https://www.ebi.ac.uk/pdbsum/4bnf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bnf 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=4bnf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bnf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bnf RCSB], [http://www.ebi.ac.uk/pdbsum/4bnf PDBsum]</span></td></tr> | + | |
| | </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 4bnf" 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 n315]] | + | [[Category: Large Structures]] |
| - | [[Category: Bommineni, G R]] | + | [[Category: Staphylococcus aureus subsp. aureus N315]] |
| - | [[Category: Chang, A]] | + | [[Category: Bommineni GR]] |
| - | [[Category: Kisker, C]] | + | [[Category: Chang A]] |
| - | [[Category: Schiebel, J]] | + | [[Category: Kisker C]] |
| - | [[Category: Tonge, P J]] | + | [[Category: Schiebel J]] |
| - | [[Category: Fatty acid biosynthesis]]
| + | [[Category: Tonge PJ]] |
| - | [[Category: Lipid synthesis]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Safabi]]
| + | |
| - | [[Category: Short-chain dehydrogenase/reductase superfamily]]
| + | |
| Structural highlights
Function
A0A0H3JLH9_STAAN
Publication Abstract from PubMed
Drug-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 Also
References
- ↑ Chang A, Schiebel J, Yu W, Bommineni GR, Pan P, Baxter MV, Khanna A, Sotriffer CA, Kisker CF, Tonge PJ. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex. Biochemistry. 2013 May 22. PMID:23697754 doi:10.1021/bi400413c
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