1ybg
From Proteopedia
(New page: 200px<br /><applet load="1ybg" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ybg, resolution 2.6Å" /> '''MurA inhibited by a d...) |
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| - | [[Image:1ybg.gif|left|200px]]<br /><applet load="1ybg" size=" | + | [[Image:1ybg.gif|left|200px]]<br /><applet load="1ybg" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1ybg, resolution 2.6Å" /> | caption="1ybg, resolution 2.6Å" /> | ||
'''MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid'''<br /> | '''MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid'''<br /> | ||
==Overview== | ==Overview== | ||
| - | MurA (UDP-N-acetylglucosamine enolpyruvyl transferase, EC 2.5.1.7) | + | 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== | ==About this Structure== | ||
| - | 1YBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Enterobacter_cloacae Enterobacter cloacae] with TAV as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/UDP-N-acetylglucosamine_1-carboxyvinyltransferase UDP-N-acetylglucosamine 1-carboxyvinyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.7 2.5.1.7] Full crystallographic information is available from [http:// | + | 1YBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Enterobacter_cloacae Enterobacter cloacae] with <scene name='pdbligand=TAV:'>TAV</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/UDP-N-acetylglucosamine_1-carboxyvinyltransferase UDP-N-acetylglucosamine 1-carboxyvinyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.7 2.5.1.7] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YBG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: UDP-N-acetylglucosamine 1-carboxyvinyltransferase]] | [[Category: UDP-N-acetylglucosamine 1-carboxyvinyltransferase]] | ||
| - | [[Category: Abdul-Latif, F | + | [[Category: Abdul-Latif, F A.]] |
[[Category: Delachaume, C.]] | [[Category: Delachaume, C.]] | ||
[[Category: Eschenburg, S.]] | [[Category: Eschenburg, S.]] | ||
[[Category: Fassy, F.]] | [[Category: Fassy, F.]] | ||
| - | [[Category: Priestman, M | + | [[Category: Priestman, M A.]] |
[[Category: Schonbrunn, E.]] | [[Category: Schonbrunn, E.]] | ||
[[Category: TAV]] | [[Category: TAV]] | ||
[[Category: inside-out alpha-beta barrel]] | [[Category: inside-out alpha-beta barrel]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:03:38 2008'' |
Revision as of 14:03, 21 February 2008
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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 with as ligand. Active as UDP-N-acetylglucosamine 1-carboxyvinyltransferase, with EC number 2.5.1.7 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
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