Transcript Macromolecular Structure Database group

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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"
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MSDsite
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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.
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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.
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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
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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/
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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
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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
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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
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Statistics search
Ligand
binding
Atomic bonds
Interactive
Charts
Environment
binding
Sequence
pattern
binding
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Search method
Search front
form
Statistics
search
Result list
Detail views
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MSDsite interface
Query
editor
Filters
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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
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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.
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Example
Pattern is defined as : HIS-any-HIS-GLU
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Hit List Help
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Hit List Visualization tools
AstexViewer@MSD-EBI :
Default PDB viewer: chemical/x-pdb.
RasMol script viewer: application/x-rasmol.
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Searched site visualization
AstexViewer[tm]
Groups menu
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Hit List Link to Details
Bound molecules form
Goto Site details
Sequence from
Atomic bonds
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Detail forms header
Links to the other
views of the same
PDB entry
Ligand binding
statistics
Switch on/off
undefined bonds
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Sequence form
Show site
search for PDB entries with the
same hetero ID and similar
environment
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Bound molecules form
Ligands that
match a search
creteria
Environment
statistics
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Environment binding statistics
Filters
HIS HIS HIS
Trnasformed to
HIS>C HIS>C HIS>I
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Bound molecules form
Bonds details
on atomic level
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Atomic bonds view
Atomic bonds
statistics
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Atomic bonds statistics
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Detail forms header
Ligand binding
statistics
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Ligand binding statistics
Filters
Distribution
type
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Ligand binding statistics –
distribution by whole
environment
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Pattern binding statistics
Pattern: H-x-H-E
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3D aligned views
 Superimposed by ligand
 Superimposed by environment
 Superimposed by pattern
 Superimposed by active site
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3D aligned views
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3D aligned views – EBIAstexViewer[tm]
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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
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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.