An enriched structural kinase database to enable kinome-wide structure-based analyses and drug discovery.
The development of a kinase structural database, the kinase knowledge base (KKB), is described. It covers all human kinase domain structures that have been deposited in the Protein Data Bank. All structures are renumbered using a common scheme, which enables efficient cross-comparisons and multiple queries of interest to the kinase field. The common numbering scheme is also used to automatically annotate conserved residues and motifs, and conformationally classify the structures based on the DFG-loop and Helix C. Analyses of residue conservation in the ATP binding site using the full human-kinome-sequence alignment lead to the identification of a conserved hydrogen bond between the hinge region backbone and a glycine in the specificity surface. Furthermore, 90% of kinases are found to have at least one stabilizing interaction for the hinge region, which has not been described before.
Brooijmans
Natasja
N
Chemical Sciences, Wyeth Research, Pearl River, New York 10965, USA. reprints@prodigy.net
Chang
Yu-Wei
YW
Mobilio
Dominick
D
Denny
Rajiah A
RA
Humblet
Christine
C
D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D010770:Phosphotransferases / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding
D008024:Ligands; D010770:Phosphotransferases