Journal
JOURNAL OF PROTEOME RESEARCH
Volume 9, Issue 9, Pages 4433-4442Publisher
AMER CHEMICAL SOC
DOI: 10.1021/pr100662s
Keywords
distorted P-loop; hydrophobic motif; AGC kinase [cAMP-dependent protein kinase (PKA)/protein; kinase G/protein kinase C (PKC)]; kinase structure space; atom preference; conformational plasticity
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Funding
- National Science Foundation [EPS-0556308, EPS-0903787]
- NIH National Center for Research Resources [C06 RR-14503-01]
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Structure-based drug design of protein-kinase inhibitors has been facilitated by availability of an enormous number of structures in the Protein Databank (PDB), systematic analyses of which can provide insight into the factors that govern ligand-protein kinase interactions and into the conformational variability of the protein kinases. In this study, a nonredundant database containing 755 unique, curated, and annotated PDB protein kinase-inhibitor complexes (each consisting of a single protein kinase chain, a ligand, and water molecules around the ligand) was created. With this dataset, analyses were performed of protein conformational variability and interactions of ligands with 11 P-loop residues. Analysis of ligand-protein interactions included ligand atom preference, ligand-protein hydrogen bonds, and the number and position of crystallographic water molecules around important P-loop residues. Analysis of variability in the conformation of the P-loop considered backbone and side-chain dihedral angles, and solvent accessible surface area (SASA). A distorted conformation of the P-loop was observed for some of the protein kinase structures. Lower SASA was observed for the hydrophobic residue in of several members of the AGC family of protein kinases. Our systematic studies were performed amino acid-by-amino acid, which is unusual for analyses of protein kinase-inhibitor complexes.
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