6wii | pdb_00006wii

Crystal structure of the K. pneumoniae LpxH/JH-LPH-41 complex

spinqualitylabelsall models 6wii, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6wii is a 1 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: DMS, GOL, MN, U2V Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LPXH_KLEP7 Hydrolyzes the pyrophosphate bond of UDP-2,3-diacylglucosamine to yield 2,3-diacylglucosamine 1-phosphate (lipid X) and UMP by catalyzing the attack of water at the alpha-P atom. Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.[HAMAP-Rule:MF_00575] Publication Abstract from PubMed The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens. Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.,Kwak SH, Cochrane CS, Ennis AF, Lim WY, Webster CG, Cho J, Fenton BA, Zhou P, Hong J Bioorg Chem. 2020 Jun 30;102:104055. doi: 10.1016/j.bioorg.2020.104055. PMID:32663666 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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