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1ybg
From Proteopedia
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'''MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid''' | '''MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid''' | ||
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[[Category: Priestman, M A.]] | [[Category: Priestman, M A.]] | ||
[[Category: Schonbrunn, E.]] | [[Category: Schonbrunn, E.]] | ||
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 16:06:44 2008'' | |
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Revision as of 13:06, 3 May 2008
MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid
Overview
MurA (UDP-N-acetylglucosamine enolpyruvyl transferase, EC 2.5.1.7) catalyzes the first committed step in the synthesis of the bacterial cell wall. It is the target of the naturally occurring, broad-spectrum antibiotic fosfomycin. Fosfomycin, an epoxide, is a relatively poor drug because an ever-increasing number of bacteria have developed resistance to fosfomycin. Thus, there is a critical need for the development of novel drugs that target MurA by a different molecular mode of action. We have identified a new scaffold of potent MurA inhibitors, derivatives of 5-sulfonoxy-anthranilic acid, using high-throughput screening. T6361 and T6362 are competitive inhibitors of MurA with respect to the first substrate, UDP-N-acetylglucosamine (UNAG), with a K(i) of 16 microM. The crystal structure of the MurA.T6361 complex at 2.6 angstrom resolution, together with fluorescence data, revealed that the inhibitor targets a loop, Pro112 to Pro121, that is crucial for the structural changes of the enzyme during catalysis. Thus, this new class of MurA inhibitors is not active site-directed but instead obstructs the transition from the open (unliganded) to the closed (UNAG-liganded) enzyme form. The results provide evidence for the existence of a MurA.UNAG collision complex that may be specifically targeted by small molecules different from ground-state analogs of the enzymatic reaction.
About this Structure
1YBG is a Single protein structure of sequence from Enterobacter cloacae. Full crystallographic information is available from OCA.
Reference
A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA)., Eschenburg S, Priestman MA, Abdul-Latif FA, Delachaume C, Fassy F, Schonbrunn E, J Biol Chem. 2005 Apr 8;280(14):14070-5. Epub 2005 Feb 8. PMID:15701635 Page seeded by OCA on Sat May 3 16:06:44 2008
