Bringing Structure to Biology:
Small Molecules and the PDBe
Protein Data Bank in Europe
www.pdbe.org
PDBe overview
• PDB is a core molecular database at EMBL-EBI
• PDBe is a founding partner of Worldwide Protein Data
Bank (wwPDB)
• Founder of Electron Microscopy Data Bank (EMDB)
• Mission: Bringing Structure to Biology
• Major activities:
• Deposition and annotation site for structural data on
biomacromolecules (X-ray, NMR, EM)
• Integrated resource of high-quality macromolecular structural
data and related information
• Provide tools and services for accessing, exploiting and
disseminating structural data to the wider biomedical community
Protein Data Bank in Europe
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PDB Depositions
10,000th PDBe annotated
structure - April 2011 (2yf6)
www.pdbe.org/2yf6
Protein Data Bank in Europe
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Chemical Component Dictionary
• Compounds in the PDB
• Small molecules bound to macromolecules
• Individual components of macromolecules
• wwPDB maintains dictionary
descriptions for all unique chemical
components
• Name, synonyms, formula, SMILES, …
• Atoms and bonds
• Ideal and representative coordinates
• Each new component assigned a
unique 3-letter identifier
• Release coincides with the release of the
parent PDB entry
Protein Data Bank in Europe
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Molecule search options
•
•
•
•
Compound name
Ligand 3-letter code
SMILES
Formula (exact or range)
e.g. C6-10 N4 O2 S0
• Chemical substructure
www.pdbe.org/chem
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PDBe Home Page
Protein Data Bank in Europe
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Ligands and the PDBe
Open
chemistry
sketchpad
Protein Data Bank in Europe
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Ligands and the PDBe
Protein Data Bank in Europe
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Ligands and the PDBe
Protein Data Bank in Europe
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2D Ligand Interaction Diagrams
www.pdbe.org/leview
• Interaction diagrams
for any given PDB
entry
• Interactive control of
distance criteria
• Diagram customisation
• Image export
png, jpg, eps…
S-benzyl-glutathione (GSB) Human Glyoxalase inhibitor (1guh)
Protein Data Bank in Europe
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PDBeXpress: rapid access to protein-ligand
interaction statistics
• Understand and assess binding site interactions
• Provide chemists with quick answers to common questions
without the need to construct complex search queries
• What residues interact?
• Which enzymes interact?
• What binds here?
• www.pdbe.org/express
Protein Data Bank in Europe
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What residues interact?
• PDB three-letter ligand code
• Ligand name
Protein Data Bank in Europe
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RTL - Retinol
What residues interact?
RTL - Retinol
Protein Data Bank in Europe
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Which enzymes interact?
• PDB three-letter ligand code
• Ligand name
Protein Data Bank in Europe
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MAN – Mannose
Which enzymes interact?
• PDB three-letter ligand code
• Ligand name
Protein Data Bank in Europe
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MAN – Mannose
What binds here?
• Search for ligands that interact with a given set of residues
• Can specify a partial or exact binding environment
Protein Data Bank in Europe
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What binds here?
Protein Data Bank in Europe
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PDBeMotif: powerful and flexible searching
• PDBeXpress modules driven by PDBeMotif
• PDBeMotif allows to combine protein sequence, chemical structure
and 3D data in a single search
Protein Data Bank in Europe
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PDBeMotif: powerful and flexible searching
• construct queries based on • ligands and their 3D environment
• secondary structure elements and small 3D motifs
• protein φ/ψ angle sequences - sequential representation of the
protein geometry
• results can be analysed against UniProt, CATH, PFAM or EC
Protein Data Bank in Europe
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Ligands need careful validation
• CCDC analysis of ligand geometries (using Relibase+/Mogul/EDS)
• Around 20% of recently determined structures have geometric errors
that could potentially cause a misleading interpretation of the binding
interactions
Wrong
Unusual/Strained
Correct
Liebeschuetz, J.W., Hennemann, J. The good, the bad and the twisted: A survey of ligand geometry in protein crystal structures
J. Comput. Aid. Mol. Des., 26, 169-183 (2012)
Protein Data Bank in Europe
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The solution…
• Mogul – a Knowledge-based library of molecular geometry derived
from the Cambridge Structural Database (CSD)
• Enables rapidly validation of the complete geometry of a given query
structure and identification of unusual features
Protein Data Bank in Europe
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Protein Data Bank in Europe
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MoU with CCDC
• wwPDB/CCDC Memorandum of Understanding
• wwPDB gets to use Mogul for validation of all current and future
compounds in the PDB
• wwPDB gets to incorporate and redistribute CSD coordinates for
all current and future ligand compounds in the PDB
• wwPDB gets to use Mogul and CSD coordinates to derive
dictionaries for all current and future compounds in the PDB
Protein Data Bank in Europe
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Prevention is the best cure
• Thanks to collaboration with CCDC
• We can add CSD coordinates for all existing small molecules in
the PDB (and variants, e.g. D-amino acids) that also occur in the
CSD
• We can use these coordinates and Mogul to derive refinement
dictionaries
• Grade (Global Phasing; uses Mogul and RM1)
• Will improve quality and consistency of the archive
• We can provide reasonable starting coordinates and refinement
dictionaries for all existing compounds in the PDB
Protein Data Bank in Europe
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Future of the PDB?
• At present PDB is a historic archive
• We have to accept and distribute everything
• “Archive” – i.e., what was described in the literature
• Essentially provider-centric
• We capture X-ray detector type but not ligand function…
• Organised by entry rather than molecule/complex/…
• Shifting user communities/demands
• We must serve the consumers of structural data (non-experts)
• Don’t think in terms of PDB entry codes
• Can’t tell a good from a bad model
Protein Data Bank in Europe
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PDBe Team February 2012
Protein Data Bank in Europe
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Funding
Protein Data Bank in Europe
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Thank you!
• Tutorials…
http://www.ebi.ac.uk/pdbe/resources/educationTabContent/tutorials/PDBeChem.pdf
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http://www.ebi.ac.uk/pdbe/docs/Tutorials/PDBeChem.html
• Contact us…
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Protein Data Bank in Europe
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