PDBsum entry 5u3b

Hydrolase

PDB id: 5u3b

Contents

Protein chains

297 a.a.

Ligands

7TD ×2

EPE ×2

Metals

_ZN ×2

Waters ×282

PDB id:

5u3b

Name:

Hydrolase

Title:

Pseudomonas aeruginosa lpxc in complex with nvs-lpxc-01

Structure:

Udp-3-o-acyl-n-acetylglucosamine deacetylase. Chain: a, b. Synonym: udp-3-o-acyl-glcnac deacetylase,udp-3-o-[r-3- hydroxymyristoyl]-n-acetylglucosamine deacetylase. Engineered: yes

Source:

Pseudomonas aeruginosa (strain atcc 15692 / dsm 22644 / cip 104116 / jcm 14847 / lmg 12228 / 1c / prs 101 / pao1). Organism_taxid: 208964. Strain: atcc 15692 / dsm 22644 / cip 104116 / jcm 14847 / lmg 12228 / 1c / prs 101 / pao1. Gene: lpxc, enva, pa4406. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.187 R-free: 0.213

Authors:

E.R.Sprague

Key ref:

G.Piizzi et al. (2017). Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC. J Med Chem, 60, 5002-5014. PubMed id: 28549219 DOI: 10.1021/acs.jmedchem.7b00377

Date:

01-Dec-16 Release date: 07-Jun-17

Protein chains

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: 297 a.a.

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/acs.jmedchem.7b00377

J Med Chem 60:5002-5014 (2017)

PubMed id: 28549219

Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.

G.Piizzi, D.T.Parker, Y.Peng, M.Dobler, A.Patnaik, S.Wattanasin, E.Liu, F.Lenoir, J.Nunez, J.Kerrigan, D.McKenney, C.Osborne, D.Yu, L.Lanieri, J.Bojkovic, J.Dzink-Fox, M.D.Lilly, E.R.Sprague, Y.Lu, H.Wang, S.Ranjitkar, L.Xie, B.Wang, M.Glick, L.G.Hamann, R.Tommasi, X.Yang, C.R.Dean.

ABSTRACT

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.