PDBsum entry 4lcf

Hydrolase/antibiotic

PDB id: 4lcf

Contents

Protein chain

298 a.a.

Ligands

1WL

NO3 ×11

Metals

_ZN ×3

Waters ×296

PDB id:

4lcf

Name:

Hydrolase/antibiotic

Title:

Crystal structure of the pseudomonas aeruginosa lpxc/lpc-014 complex

Structure:

Udp-3-o-[3-hydroxymyristoyl] n-acetylglucosamine deacetylase. Chain: a. Fragment: unp residues 1-299. Synonym: protein enva, udp-3-o-acyl-glcnac deacetylase. Engineered: yes. Mutation: yes

Source:

Pseudomonas aeruginosa. Organism_taxid: 208964. Strain: atcc 15692 / pao1 / 1c / prs 101 / lmg 12228. Gene: enva, lpxc, pa4406. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.60Å R-factor: 0.192 R-free: 0.220

Authors:

C.-J.Lee,P.Zhou

Key ref:

X.Liang et al. (2013). Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. J Med Chem, 56, 6954-6966. PubMed id: 23914798 DOI: 10.1021/jm4007774

Date:

21-Jun-13 Release date: 21-Aug-13

Protein chain

P47205  (LPXC_PSEAE) -  UDP-3-O-acyl-N-acetylglucosamine deacetylase from Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)

Seq: 303 a.a.

Struc: 298 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.5.1.108 - UDP-3-O-acyl-N-acetylglucosamine deacetylase.
• Reaction: a UDP-3-O-[(3R)-3-hydroxyacyl]-N-acetyl-alpha-D-glucosamine + H2O = a UDP-3-O-[(3R)-3-hydroxyacyl]-alpha-D-glucosamine + acetate
• Cofactor: Zn(2+)

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

Key reference

DOI no: 10.1021/jm4007774

J Med Chem 56:6954-6966 (2013)

PubMed id: 23914798

Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors.

X.Liang, C.J.Lee, J.Zhao, E.J.Toone, P.Zhou.

ABSTRACT

The zinc-dependent deacetylase LpxC catalyzes the committed step of lipid A biosynthesis in Gram-negative bacteria and is a validated target for the development of novel antibiotics to combat multidrug-resistant Gram-negative infections. Many potent LpxC inhibitors contain an essential threonyl-hydroxamate headgroup for high-affinity interaction with LpxC. We report the synthesis, antibiotic activity, and structural and enzymatic characterization of novel LpxC inhibitors containing an additional aryl group in the threonyl-hydroxamate moiety, which expands the inhibitor-binding surface in LpxC. These compounds display enhanced potency against LpxC in enzymatic assays and superior antibiotic activity against Francisella novicida in cell culture. The comparison of the antibiotic activities of these compounds against a leaky Escherichia coli strain and the wild-type strain reveals the contribution of the formidable outer-membrane permeability barrier that reduces the compounds efficacy in cell culture and emphasizes the importance of maintaining a balanced hydrophobicity and hydrophilicity profile in developing effective LpxC-targeting antibiotics.