3swd | pdb_00003swd

E. coli MurA in complex with UDP-N-acetylmuramic acid and covalent adduct of PEP with Cys115

spinqualitylabelsall models 3swd, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3swd is a 12 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: EPZ, IAS, QPA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MURA_ECOLI Cell wall formation. Adds enolpyruvyl to UDP-N-acetylglucosamine. Target for the antibiotic phosphomycin.[HAMAP-Rule:MF_00111] Publication Abstract from PubMed The enzyme MurA has been an established antibiotic target since the discovery of fosfomycin, which specifically inhibits MurA by covalent modification of the active site residue Cys115. Early biochemical studies established that Cys115 also covalently reacts with substrate phosphoenolpyruvate (PEP) to yield a phospholactoyl adduct, but the structural and functional consequences of this reaction remained obscure. We captured and depicted the Cys115-PEP adduct of E. cloacace MurA in various reaction states by X-ray crystallography. The data suggest that cellular MurA predominantly exists in a tightly locked complex with UDP-N-acetylmuramic acid (UNAM), the product of the MurB reaction, with PEP covalently attached to Cys115. The uniqueness and rigidity of this dormant complex was previously not recognized and presumably accounts for the failure of drug discovery efforts towards the identification of novel and effective MurA inhibitors. We demonstrate that recently published crystal structures of MurA from various organisms determined by different laboratories were indeed misinterpreted and actually contain UNAM and covalently bound PEP. The Cys115-PEP adduct was also captured in vitro during the reaction of free MurA and substrate UDP-N-acetylglucosamine (UNAG) or isomer UDP-N-acetylgalactosamine. The now available series of crystal structures allows a comprehensive view of the reaction cycle of MurA. It appears that the covalent reaction of MurA with PEP fulfills dual functions by tightening the complex with UNAM for the efficient feedback regulation of murein biosynthesis and by priming the PEP molecule for instantaneous reaction with substrate UNAG. Functional consequence of the covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA).,Zhu JY, Yang Y, Han H, Betzi S, Olesen S, Marsilio F, Schonbrunn E J Biol Chem. 2012 Feb 29. PMID:22378791 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoylpyruvate transferase 3D structures

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