Bringing Structure to Biology Small Molecules and the

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 (ww. PDB) • 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 www. pdbe. org

PDB Depositions 10, 000 th PDBe annotated structure - April 2011 (2 yf 6) www. pdbe. org/2 yf 6 Protein Data Bank in Europe www. pdbe. org

Chemical Component Dictionary • Compounds in the PDB • Small molecules bound to macromolecules • Individual components of macromolecules • ww. PDB 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 www. pdbe. org

Molecule search options • • Compound name Ligand 3 -letter code SMILES Formula (exact or range) e. g. C 6 -10 N 4 O 2 S 0 • Chemical substructure www. pdbe. org/chem Protein Data Bank in Europe www. pdbe. org

PDBe Home Page http: //www. ebi. ac. uk/pdbe Protein Data Bank in Europe www. pdbe. org

Ligands and the PDBe Open chemistry sketchpad Protein Data Bank in Europe www. pdbe. org

Ligands and the PDBe Protein Data Bank in Europe www. pdbe. org

2 D 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 (1 guh) Protein Data Bank in Europe www. pdbe. org

PDBe. Xpress: rapid access to protein-ligand interaction statistics • Understand 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 www. pdbe. org

What residues interact? • PDB three-letter ligand code • Ligand name Protein Data Bank in Europe www. pdbe. org RTL - Retinol

What residues interact? RTL - Retinol Protein Data Bank in Europe www. pdbe. org

Which enzymes interact? • PDB three-letter ligand code • Ligand name Protein Data Bank in Europe www. pdbe. org 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 www. pdbe. org

What binds here? Protein Data Bank in Europe www. pdbe. org

PDBe. Motif: powerful and flexible searching • PDBe. Xpress modules driven by PDBe. Motif • PDBe. Motif allows to combine protein sequence, chemical structure and 3 D data in a single search Protein Data Bank in Europe www. pdbe. org

PDBe. Motif: powerful and flexible searching • construct queries based on - • ligands and their 3 D environment • secondary structure elements and small 3 D motifs • protein φ/ψ angle sequences - sequential representation of the protein geometry • results can be analysed against Uni. Prot, CATH, PFAM or EC Protein Data Bank in Europe www. pdbe. org

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 www. pdbe. org

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 www. pdbe. org

Protein Data Bank in Europe www. pdbe. org

Mo. U with CCDC • ww. PDB/CCDC Memorandum of Understanding • ww. PDB gets to use Mogul for validation of all current and future compounds in the PDB • ww. PDB gets to incorporate and redistribute CSD coordinates for all current and future ligand compounds in the PDB • ww. PDB gets to use Mogul and CSD coordinates to derive dictionaries for all current and future compounds in the PDB Protein Data Bank in Europe www. pdbe. org

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 RM 1) • 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 www. pdbe. org

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 www. pdbe. org

PDBe Team February 2012 Protein Data Bank in Europe www. pdbe. org

Funding Protein Data Bank in Europe www. pdbe. org

Thank you! • Tutorials… http: //www. ebi. ac. uk/pdbe/resources/education. Tab. Content/tutorials/PDBe. Chem. pdf http: //www. ebi. ac. uk/pdbe-apps/quips? story=Xmas. Factor&auxpage=Xmas. Chem. Tut http: //www. ebi. ac. uk/pdbe/docs/Tutorials/PDBe. Chem. html • Contact us… www. pdbe. org pdbehelp@ebi. ac. uk • Follow us… http: //www. facebook. com/proteindatabank http: //twitter. com/PDBeurope Protein Data Bank in Europe www. pdbe. org