2aq7
From Proteopedia
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'''Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli''' | '''Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli''' | ||
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[[Category: Shenoy, G.]] | [[Category: Shenoy, G.]] | ||
[[Category: Zhang, Y M.]] | [[Category: Zhang, Y M.]] | ||
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:20:20 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 16:20, 3 May 2008
Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli
Overview
Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.
About this Structure
2AQ7 is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli., Kim P, Zhang YM, Shenoy G, Nguyen QA, Boshoff HI, Manjunatha UH, Goodwin MB, Lonsdale J, Price AC, Miller DJ, Duncan K, White SW, Rock CO, Barry CE 3rd, Dowd CS, J Med Chem. 2006 Jan 12;49(1):159-71. PMID:16392800 Page seeded by OCA on Sat May 3 19:20:20 2008
