4J3D

Pseudomonas aeruginosa LpxC in complex with a hydroxamate inhibitor

Summary for 4J3D

• Entry DOI: 10.2210/pdb4j3d/pdb
• Descriptor: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, N~1~-hydroxy-N~5~-(3-hydroxypropyl)-N~2~-[4-(phenylethynyl)benzoyl]-L-glutamamide, ... (4 entities in total)
• Functional Keywords: lpxc, metalloamidase, udp-3-o-(r-3-hydroxymyristoyl)-n-acetylglucosamine deacetylase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 66925.30

Authors

Lahiri, S. (deposition date: 2013-02-05, release date: 2013-04-03, Last modification date: 2024-02-28)

Primary citation

Hale, M.R.,Hill, P.,Lahiri, S.,Miller, M.D.,Ross, P.,Alm, R.,Gao, N.,Kutschke, A.,Johnstone, M.,Prince, B.,Thresher, J.,Yang, W.
Exploring the UDP pocket of LpxC through amino acid analogs.
Bioorg.Med.Chem.Lett., 23:2362-2367, 2013

PubMed Abstract: Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs.

PubMed: 23499237
DOI: 10.1016/j.bmcl.2013.02.055

Experimental method

X-RAY DIFFRACTION (2 Å)