3P76

X-ray crystal structure of Aquifex aeolicus LpxC complexed SCH1379777

Summary for 3P76

• Entry DOI: 10.2210/pdb3p76/pdb
• Descriptor: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, IMIDAZOLE, N-[(1S,2R)-2-hydroxy-1-(hydroxycarbamoyl)propyl]-4-[4-(phenylethynyl)phenyl]piperidine-1-carboxamide, ... (5 entities in total)
• Functional Keywords: amidohydrolases, amino acid motifs, binding sites, drug design, enzyme inhibitors, escherichia coli proteins, hydrophobicity, lipid a, protein conformation, protein folding, recombinant fusion proteins, structure-activity relationship, hydrolase
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 1
• Total formula weight: 31610.90

Authors

Orth, P. (deposition date: 2010-10-12, release date: 2011-02-09, Last modification date: 2023-09-06)

Primary citation

Faruk Mansoor, U.,Vitharana, D.,Reddy, P.A.,Daubaras, D.L.,McNicholas, P.,Orth, P.,Black, T.,Arshad Siddiqui, M.
Design and synthesis of potent Gram-negative specific LpxC inhibitors.
Bioorg.Med.Chem.Lett., 21:1155-1161, 2011

PubMed Abstract: Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme's catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding 'warheads' lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.

PubMed: 21273067
DOI: 10.1016/j.bmcl.2010.12.111

Experimental method

X-RAY DIFFRACTION (1.93 Å)