4d41: Difference between revisions
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==Crystal structure of S. aureus FabI in complex with NADP and 5-hexyl- 2-(4-nitrophenoxy)phenol== | ==Crystal structure of S. aureus FabI in complex with NADP and 5-hexyl- 2-(4-nitrophenoxy)phenol== | ||
<StructureSection load='4d41' size='340' side='right' caption='[[4d41]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='4d41' size='340' side='right' caption='[[4d41]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d42|4d42]], [[4d43|4d43]], [[4d44|4d44]], [[4d45|4d45]], [[4d46|4d46]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d42|4d42]], [[4d43|4d43]], [[4d44|4d44]], [[4d45|4d45]], [[4d46|4d46]]</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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d41 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d41 RCSB], [http://www.ebi.ac.uk/pdbsum/4d41 PDBsum]</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=4d41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d41 OCA], [http://pdbe.org/4d41 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d41 RCSB], [http://www.ebi.ac.uk/pdbsum/4d41 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d41 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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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 4d41" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
Revision as of 20:28, 18 January 2017
Crystal structure of S. aureus FabI in complex with NADP and 5-hexyl- 2-(4-nitrophenoxy)phenolCrystal structure of S. aureus FabI in complex with NADP and 5-hexyl- 2-(4-nitrophenoxy)phenol
Structural highlights
Publication Abstract from PubMedOne third of all drugs in clinical use owe their pharmacological activity to the functional inhibition of enzymes, highlighting the importance of enzymatic targets for drug development. Because of the close relationship between inhibition and catalysis, understanding the recognition and turnover of enzymatic substrates is essential for rational drug design. Although the Staphylococcus aureus enoyl-acyl carrier protein reductase (saFabI) involved in bacterial fatty acid biosynthesis constitutes a very promising target for the development of novel, urgently needed anti-staphylococcal agents, the substrate binding mode and catalytic mechanism remained unclear for this enzyme. Using a combined crystallographic, kinetic, and computational approach, we have explored the chemical properties of the saFabI binding cavity, obtaining a consistent mechanistic model for substrate binding and turnover. We identified a water-molecule network linking the active site with a water basin inside the homo-tetrameric protein, which seems to be crucial for the closure of the flexible substrate binding loop as well as for an effective hydride and proton transfer during catalysis. On the basis of our results, we also derive a new model for the FabI-ACP complex that reveals how the ACP-bound acyl-substrate is injected into the FabI binding crevice. These findings support the future development of novel FabI inhibitors that target the FabI-ACP interface leading to the disruption of the interaction between these two proteins. An Ordered Water Channel in Staphylococcus aureus FabI: Unraveling the Mechanism of Substrate Recognition and Reduction.,Schiebel J, Chang A, Merget B, Bommineni GR, Yu W, Spagnuolo LA, Baxter MV, Tareilus M, Tonge PJ, Kisker C, Sotriffer CA Biochemistry. 2015 Mar 3. PMID:25706582[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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