3le8

Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.70 Angstrom resolution in complex with 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid

spinqualitylabelsall models 3le8, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3le8 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: 2B5, EDO, EOH, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PANC_MYCTU Catalyzes the condensation of pantoate with beta-alanine in an ATP-dependent reaction via a pantoyl-adenylate intermediate. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Fragment-based methods are a new and emerging approach for the discovery of protein binders that are potential new therapeutic agents. Several ways of utilizing structural information to guide the inhibitor assembly have been explored to date. One of the approaches, application of interligand Overhauser effect (ILOE) observations, is of particular interest, as it does not require the availability of a three-dimensional protein structure and is an NMR-based method that can be applied to targets that cannot be observed directly because of their size. Fragments, as small and often hydrophobic molecules, suffer from problems including compound aggregation in an aqueous environment and nonspecific binding contributions, especially when screened at higher concentrations suitable for ILOE observations. Here we report how this problem can be overcome by applying a step-by-step iterative procedure that includes the application of optimized probe molecules with known binding modes to elucidate the unknown binding modes of fragments. An enzyme substrate with well-characterized binding was used as a starting point, and the relative binding modes of modified fragments derived from ILOE observations were used to guide the fragment linking, leading to a potent inhibitor of our model system, Mycobacterium tuberculosis pantothenate synthetase, a potential drug target. We have supported our NMR data with crystal structures, thus establishing the guidelines for optimizing the ILOE observations. This model study should expand the application of the technique in drug discovery. Optimization of the interligand overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase.,Sledz P, Silvestre HL, Hung AW, Ciulli A, Blundell TL, Abell C J Am Chem Soc. 2010 Apr 7;132(13):4544-5. PMID:20232910 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pantothenate synthetase

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