5wly

E. coli LpxH- 8 mutations

spinqualitylabelsall models 5wly, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5wly is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: CL, EDO, FMT, MN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LPXH_ECOLI 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 (PubMed:12000770). Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell (PubMed:12000770, PubMed:12000771). Is essential for E.coli growth (PubMed:12000771). Does not cleave the unacylated UDP-GlcNAc, the mono-acylated UDP-3-O-(R)-3-hydroxymyristoyl-GlcNAc, and CDP-diacylglycerol (PubMed:12000770). Publication Abstract from PubMed Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen-deuterium exchange mass spectrometry provided evidence for a highly flexible substrate-binding cap in LpxH. Furthermore, molecular dynamics simulations disclosed how the helices of the cap may open to allow substrate entry. The predicted opening mechanism was supported by activity assays of LpxH variants. Finally, we confirmed biochemically that LpxH is inhibited by a previously identified antibacterial compound, determined the potency of this inhibitor, and modeled its binding mode in the LpxH active site. In summary, our work provides evidence that the substrate-binding cap of LpxH is highly dynamic thus allowing for facile substrate binding and product release between the capping helices. Our results also pave the way for the rational design of more potent LpxH inhibitors. The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release.,Bohl TE, Ieong P, Lee JK, Lee T, Kankanala J, Shi K, Demir O, Kurahashi K, Amaro RE, Wang Z, Aihara H J Biol Chem. 2018 Apr 6. pii: RA118.002503. doi: 10.1074/jbc.RA118.002503. PMID:29626094 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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