3rv7: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of a M. tuberculosis Salicylate Synthase, MbtI, in Complex with an Inhibitor with Isopropyl R-Group== | |||
<StructureSection load='3rv7' size='340' side='right' caption='[[3rv7]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3rv7]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RV7 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RVB:3-{[(1Z)-1-CARBOXY-3-METHYLBUT-1-EN-1-YL]OXY}-2-HYDROXYBENZOIC+ACID'>RVB</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rv6|3rv6]], [[3rv8|3rv8]], [[3rv9|3rv9]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv2386c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])</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=3rv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rv7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rv7 RCSB], [http://www.ebi.ac.uk/pdbsum/3rv7 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
MbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family. | |||
Implications of Binding Mode and Active Site Flexibility for Inhibitor Potency against the Salicylate Synthase from Mycobacterium tuberculosis.,Chi G, Manos-Turvey A, O'Connor PD, Johnston JM, Evans GL, Baker EN, Payne RJ, Lott JS, Bulloch EM Biochemistry. 2012 Jun 7. PMID:22607697<ref>PMID:22607697</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Isochorismate pyruvate lyase|Isochorismate pyruvate lyase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Bulloch, E M.M | [[Category: Bulloch, E M.M]] | ||
[[Category: Chi, G | [[Category: Chi, G]] | ||
[[Category: Lott, J S | [[Category: Lott, J S]] | ||
[[Category: Manos-Turvey, A | [[Category: Manos-Turvey, A]] | ||
[[Category: Payne, R J | [[Category: Payne, R J]] | ||
[[Category: | [[Category: Structural genomic]] | ||
[[Category: Chorismate binding]] | [[Category: Chorismate binding]] | ||
[[Category: Isomerase-isomerase inhibitor complex]] | [[Category: Isomerase-isomerase inhibitor complex]] | ||
[[Category: Salicylate synthase]] | [[Category: Salicylate synthase]] | ||
[[Category: Tbsgc]] | [[Category: Tbsgc]] | ||
Revision as of 14:04, 19 December 2014
Structure of a M. tuberculosis Salicylate Synthase, MbtI, in Complex with an Inhibitor with Isopropyl R-GroupStructure of a M. tuberculosis Salicylate Synthase, MbtI, in Complex with an Inhibitor with Isopropyl R-Group
Structural highlights
Publication Abstract from PubMedMbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family. Implications of Binding Mode and Active Site Flexibility for Inhibitor Potency against the Salicylate Synthase from Mycobacterium tuberculosis.,Chi G, Manos-Turvey A, O'Connor PD, Johnston JM, Evans GL, Baker EN, Payne RJ, Lott JS, Bulloch EM Biochemistry. 2012 Jun 7. PMID:22607697[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||