3nb7 | pdb_00003nb7

Crystal structure of Aquifex Aeolicus Peptidoglycan Glycosyltransferase in complex with Decarboxylated Neryl Moenomycin

spinqualitylabelsall models 3nb7, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3nb7 is a 1 chain structure with sequence from "aquifex_aeolicus"_huber_and_stetter_2001 "aquifex aeolicus" huber and stetter 2001. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 2oqo, 3d3h, 3nb6 Gene: aq_624, mrcA, ponA ("Aquifex aeolicus" Huber and Stetter 2001) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Moenomycin A (MmA) belongs to a family of natural products that inhibit peptidoglycan biosynthesis by binding to the peptidoglycan glycosyltransferases, the enzymes that make the glycan chains of peptidoglycan. MmA is remarkably potent, but its clinical utility has been hampered by poor physicochemical properties. Moenomycin contains three structurally distinct regions: a pentasaccharide, a phosphoglycerate, and a C25 isoprenyl (moenocinyl) lipid tail that gives the molecule its name. The phosphoglycerate moiety links the pentasaccharide to the moenocinyl chain. This moiety contains two negatively charged groups, a phosphoryl group and a carboxylate. Both the phosphoryl group and the carboxylate have previously been implicated in target binding but the role of the carboxylate has not been explored in detail. Here we report the synthesis of six MmA analogues designed to probe the importance of the phosphoglycerate. These analogues were evaluated for antibacterial and enzyme inhibitory activity; the specific contacts between the phosphoglycerate and the protein target were assessed by X-ray crystallography in conjunction with molecular modeling. Both the phosphoryl group and the carboxylate of the phosphoglycerate chain play roles in target binding. The negative charge of the carboxylate, and not its specific structure, appears to be the critical feature in binding since replacing it with a negatively charged acylsulfonamide group produces a more active compound than replacing it with the isosteric amide. Analysis of the ligand-protein contacts suggests that the carboxylate makes a critical contact with an invariant lysine in the active site. The reported work provides information and validated computational methods critical for the design of analogues based on moenomycin scaffolds. Functional and structural analysis of a key region of the cell wall inhibitor moenomycin.,Fuse S, Tsukamoto H, Yuan Y, Wang TS, Zhang Y, Bolla M, Walker S, Sliz P, Kahne D ACS Chem Biol. 2010 Jul 16;5(7):701-11. PMID:20496948 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Penicillin-binding protein 3D structures

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