Abstract
Protein kinases play a crucial role in cell signaling and are important drug targets in several therapeutic areas. The KLIFS database contains detailed structural kinase-ligand interaction information derived from all (>2900) structures of catalytic domains of human and mouse protein kinases deposited in the Protein Data Bank in order to provide insights into the structural determinants of kinase-ligand binding and selectivity. The kinase structures have been processed in a consistent manner by systematically analyzing the structural features and molecular interaction fingerprints (IFPs) of a predefined set of 85 binding site residues with bound ligands. KLIFS has been completely rebuilt and extended (>65% more structures) since its first release as a data set, including: novel automated annotation methods for (i) the assessment of ligand-targeted subpockets and the analysis of (ii) DFG and (iii) αC-helix conformations; improved and automated protocols for (iv) the generation of sequence/structure alignments, (v) the curation of ligand atom and bond typing for accurate IFP analysis and (vi) weekly database updates. KLIFS is now accessible via a website (http://klifs.vu-compmedchem.nl) that provides a comprehensive visual presentation of different types of chemical, biological and structural chemogenomics data, and allows the user to easily access, compare, search and download the data.
Highlights
Protein kinases are enzymes that modulate the biological activity and expression of proteins by catalyzing the phosphorylation of serine, threonine or tyrosine residues
With this new version KLIFS has grown from a downloadable data set to a fully featured database with a userfriendly, yet versatile, web interface
On the back end the sequence alignment, structure superposing, structure processing and kinase-ligand interaction analysis protocols have been improved and new methods have been developed for the automated annotation of subpocket-targeting by ligands, DFG and ␣C-helix conformations and the curation of ligand topologies for accurate kinase-ligand interaction analysis
Summary
Protein kinases are enzymes that modulate the biological activity and expression of proteins by catalyzing the phosphorylation of serine, threonine or tyrosine residues. The 518 human protein kinases constitute one of the largest protein families encoded within the human genome and play essential roles in the majority of cell signal transduction pathways [1]. The catalytic domains of kinases share a conserved structure, which poses a challenge for the development of small molecule drugs that can selectively target a well-defined set of kinases in order to obtain the desired (poly)pharmacological effects [4]. (August 12, 2015), 2899 structures of human and mouse catalytic kinase domains have been experimentally determined (2892 X-ray, 5 NMR and 2 EM structures; see Supplementary Table S1) that can offer insights into the structural determinants of kinase-ligand interaction and selectivity. We have collected, processed, annotated and analyzed all available structural kinase-ligand interaction information in a single, enriched and searchable web resource, KLIFS––Kinase-Ligand Interaction Fingerprints and Structures––database, to enable systematic comparison and analysis of the chemical and structural features of all available experimentally-determined protein kinase structures and their small molecule ligands (Figure 1)
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