4LCH
Crystal structure of the Pseudomonas aeruginosa LPXC/LPC-051 complex
Summary for 4LCH
| Entry DOI | 10.2210/pdb4lch/pdb |
| Related | 4LCF 4LCG |
| Descriptor | UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, (betaS)-Nalpha-{4-[4-(4-aminophenyl)buta-1,3-diyn-1-yl]benzoyl}-N,beta-dihydroxy-beta-methyl-L-tyrosinamide, ... (5 entities in total) |
| Functional Keywords | lipid a biosynthesis, lipid a synthesis, baab sandwich, lpxc, deacetylation, acyl udp-glcnac, hydroxamate, hydrolase-antibiotic complex, hydrolase/antibiotic |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 1 |
| Total formula weight | 34804.41 |
| Authors | Lee, C.-J.,Zhou, P. (deposition date: 2013-06-21, release date: 2013-08-21, Last modification date: 2024-02-28) |
| Primary citation | Liang, X.,Lee, C.J.,Zhao, J.,Toone, E.J.,Zhou, P. Synthesis, Structure, and Antibiotic Activity of Aryl-Substituted LpxC Inhibitors. J.Med.Chem., 56:6954-6966, 2013 Cited by PubMed 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. PubMed: 23914798DOI: 10.1021/jm4007774 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.596 Å) |
Structure validation
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