PDBsum entry: 1ybg

Transferase/transferase inhibitor

PDB id: 1ybg

Contents

Protein chains

419 a.a. *

Ligands

TAV ×4

Waters ×439

* Residue conservation analysis

PDB id:

1ybg

Name:

Transferase/transferase inhibitor

Title:

Mura inhibited by a derivative of 5-sulfonoxy-anthranilic ac

Structure:

Udp-n-acetylglucosamine 1-carboxyvinyltransferase chain: a, b, c, d. Synonym: enoylpyruvate transferase, udp-n-acetylglucosamine enolpyruvyl transferase, ept. Engineered: yes. Mutation: yes

Source:

Enterobacter cloacae. Organism_taxid: 550. Gene: mura, murz. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.60Å R-factor: 0.209 R-free: 0.253

Authors:

S.Eschenburg,M.A.Priestman,F.A.Abdul-Latif,C.Delachaume,F.Fa E.Schonbrunn

Key ref:

S.Eschenburg et al. (2005). A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). J Biol Chem, 280, 14070-14075. PubMed id: 15701635 DOI: 10.1074/jbc.M414412200

Date:

20-Dec-04 Release date: 15-Feb-05

Protein chains

P33038  (MURA_ENTCC) -  UDP-N-acetylglucosamine 1-carboxyvinyltransferase

Seq: 419 a.a.

Struc: 419 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.5.1.7 - UDP-N-acetylglucosamine 1-carboxyvinyltransferase.
• Pathway: Peptidoglycan Biosynthesis (Part 1)
• Reaction: Phosphoenolpyruvate + UDP-N-acetyl-D-glucosamine = phosphate + UDP-N- acetyl-3-O-(1-carboxyvinyl)-D-glucosamine

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: cytoplasm (1 term)
• Biological process: cell cycle (6 terms)
• Biochemical function: catalytic activity (4 terms)

reference

DOI no: 10.1074/jbc.M414412200

J Biol Chem 280:14070-14075 (2005)

PubMed id: 15701635

A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA).

S.Eschenburg, M.A.Priestman, F.A.Abdul-Latif, C.Delachaume, F.Fassy, E.Schönbrunn.

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.

Selected figure(s)

Figure 1.
FIG. 1. The reaction catalyzed by MurA.

Figure 2.
FIG. 2. The structures of T6361 and T6362.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 14070-14075) copyright 2005.

Figures were selected by an automated process.