Protein Data Bank in Europe Bringing Structure to Biology: Small Molecules and the PDBe

Protein Data Bank in Europe www.pdbe.org

Bringing Structure to Biology: Small Molecules and the PDBe

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

PDB Depositions

10,000th PDBe annotated structure - April 2011 (2yf6)www.pdbe.org/2yf6

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

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

PDBe Home Page http://www.ebi.ac.uk/pdbe

Ligands and the PDBe

Open chemistry sketchpad

2D Ligand Interaction Diagrams

• Interaction diagrams for any given PDB entry

• Interactive control of distance criteria

• Diagram customisation

• Image exportpng, jpg, eps…

www.pdbe.org/leview

S-benzyl-glutathione (GSB) Human Glyoxalase inhibitor (1guh)

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

What residues interact?

RTL - Retinol• PDB three-letter ligand code• Ligand name

What residues interact?

RTL - Retinol

MAN – Mannose

Which enzymes interact?

• PDB three-letter ligand code• Ligand name

MAN – Mannose

Which enzymes interact?

• PDB three-letter ligand code• Ligand name

What binds here?

• Search for ligands that interact with a given set of residues• Can specify a partial or exact binding environment

What binds here?

• PDBeXpress modules driven by PDBeMotif

• PDBeMotif allows to combine protein sequence, chemical structure and 3D data in a single search

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

PDBeMotif: powerful and flexible searching

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

Unusual/Strained

Correct

Liebeschuetz, J.W., Hennemann, J. The good, the bad and the twisted: A survey of ligand geometry in protein crystal structuresJ. Comput. Aid. Mol. Des., 26, 169-183 (2012)

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

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

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

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

PDBe Team February 2012

Funding

• Tutorials…

http://www.ebi.ac.uk/pdbe/resources/educationTabContent/tutorials/PDBeChem.pdf http://www.ebi.ac.uk/pdbe-apps/quips?story=XmasFactor&auxpage=XmasChemTut http://www.ebi.ac.uk/pdbe/docs/Tutorials/PDBeChem.html

• Contact us…www.pdbe.org

pdbehelp@ebi.ac.uk

• Follow us…

Thank you!

http://www.facebook.com/proteindatabank

http://twitter.com/PDBeurope

Protein Data Bank in Europe Bringing Structure to Biology: Small Molecules and the PDBe

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