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EMBL-EBI Adel Golovin MSDsite The project is funded by the European Commission as the TEMBLOR, contract-no. QLRI-CT2001-00015 under the RTD programme "Quality of Life and Management of Living Resources" EMBL-EBI MSDsite EMBL-EBI Introduction Many protein (and some nucleic acids) structures have evolved as a framework for an active site – where chemistry takes place. The active site is critical for the understanding the action of proteins and their role within the cell mechanism. The function, of these macromolecules can best be studied by detailed 3-dimensional knowledge of these active sites. Because the active site is a local 3D environment. EMBL-EBI Ligand environment The 3D / 1D position that defines the protein function disparate amino acids on the 1D sequence A localized volume in 3D Where chemistry/binding happens. EMBL-EBI MSD site database The MSD site database contains local structural information around all the bound ligands within the PDB All proteins deposited to the PDB are checked for ligand(s). These are HETATM & non-protein/non-nucleicacid/non-water residues. Interactions are stored within the DB The bound ligand coordinates & associated information The ligand environment (i.e. any residue that interacts) The interaction types between the ligand and environment. All sequences are checked for the registered ProSite patterns and matches are stored in the DB Fast algorithm for a pattern search is embedded into the DB EMBL-EBI Site definitions Sites are defined as a ligand environment when a ligand is presented. Sequence motifs matching is applied for site definition independently from ligands. ProSite sites http://www.expasy.org/prosite Catalytic sites atlas http://www.ebi.ac.uk/thornton-srv/databases/CSA/ Merops active sites http://merops.sanger.ac.uk/ EMBL-EBI Environment Covalent Bonds Coordinate bonds Hydrogen bonds Structure Planes DB Non-bonding Site DB Electrostatics Di-Sulphide bonds Geometry (distance, angles..) Ligand environment analysis PHE N A S P O S PHE V A L EMBL-EBI Possible site searches Define search by ligand Define search by sequence motif (pattern) Define search by metal site geometry Define search by environment has same environment has similar environment EMBL-EBI Search options Structure Protein Ligand Define target: equal/like Filter by PDB header: equal/like Sequence motif Search criteria Metal site geometry Environment exact/sub set EMBL-EBI Statistics search Ligand binding Atomic bonds Interactive Charts Environment binding Sequence pattern binding EMBL-EBI Search method Search front form Statistics search Result list Detail views EMBL-EBI MSDsite interface Query editor Filters EMBL-EBI Query generation HIS|SER:S/H>C2.0 HIS.NE2:S/S>C2.0 HIS.[N]/T>C2.0 Drawing Complex queries secondary structure Distance cut-offs Bond type Side/main chain EMBL-EBI Search service aims Form a site search criteria Provide a hit list Visualize the found sites XML technology (xpath,..) to search an XML corresponding to a PDB entry from the hit list. EMBL-EBI Example Pattern is defined as : HIS-any-HIS-GLU EMBL-EBI Hit List Help EMBL-EBI Hit List Visualization tools AstexViewer@MSD-EBI : Default PDB viewer: chemical/x-pdb. RasMol script viewer: application/x-rasmol. EMBL-EBI Searched site visualization AstexViewer[tm] Groups menu EMBL-EBI Hit List Link to Details Bound molecules form Goto Site details Sequence from Atomic bonds EMBL-EBI Detail forms header Links to the other views of the same PDB entry Ligand binding statistics Switch on/off undefined bonds EMBL-EBI Sequence form Show site search for PDB entries with the same hetero ID and similar environment EMBL-EBI Bound molecules form Ligands that match a search creteria Environment statistics EMBL-EBI Environment binding statistics Filters HIS HIS HIS Trnasformed to HIS>C HIS>C HIS>I EMBL-EBI Bound molecules form Bonds details on atomic level EMBL-EBI Atomic bonds view Atomic bonds statistics EMBL-EBI Atomic bonds statistics EMBL-EBI Detail forms header Ligand binding statistics EMBL-EBI Ligand binding statistics Filters Distribution type EMBL-EBI Ligand binding statistics – distribution by whole environment EMBL-EBI Pattern binding statistics Pattern: H-x-H-E EMBL-EBI 3D aligned views Superimposed by ligand Superimposed by environment Superimposed by pattern Superimposed by active site EMBL-EBI 3D aligned views EMBL-EBI 3D aligned views – EBIAstexViewer[tm] EMBL-EBI EMBL-EBI Summary DB of active sites has been generated Application server has been developed The DB can be searched Based on properties of the ligand environment Based on properties of the ligand Based on properties of structure and sequence of the parent protein EMBL-EBI Future sites Data generated by data mining of common packing of chemical groups is being added. (Proteins S.F.G, 49:510-528, T.J.Oldfield). This information contains about 2000 sites, 1/3 with ligands.