1YBG

MurA inhibited by a derivative of 5-sulfonoxy-anthranilic acid

Summary for 1YBG

• Entry DOI: 10.2210/pdb1ybg/pdb
• Related: 1EJC 1EJD 1EYN 1NAW 1Q3G 1UAE
• Descriptor: UDP-N-acetylglucosamine 1-carboxyvinyltransferase, N-METHYL-N-{2-[(2-NAPHTHYLSULFONYL)AMINO]-5-[(2-NAPHTHYLSULFONYL)OXY]BENZOYL}-L-ASPARTIC ACID (3 entities in total)
• Functional Keywords: inside-out alpha-beta barrel, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Enterobacter cloacae
• Cellular location: Cytoplasm : P33038
• Total number of polymer chains: 4
• Total formula weight: 181968.37

Authors

Eschenburg, S.,Priestman, M.A.,Abdul-Latif, F.A.,Delachaume, C.,Fassy, F.,Schonbrunn, E. (deposition date: 2004-12-20, release date: 2005-02-15, Last modification date: 2024-11-13)

Primary citation

Eschenburg, S.,Priestman, M.A.,Abdul-Latif, F.A.,Delachaume, C.,Fassy, F.,Schonbrunn, E.
A Novel Inhibitor That Suspends the Induced Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA).
J.Biol.Chem., 280:14070-14075, 2005

PubMed Abstract: 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.

PubMed: 15701635
DOI: 10.1074/jbc.M414412200

Experimental method

X-RAY DIFFRACTION (2.6 Å)