title: Comparative surface geometry of the protein kinase family.
abstract: Identifying conserved pockets on the surfaces of a family of proteins can provide insight into conserved geometric features and sites of protein-protein interaction. Here we describe mapping and comparison of the surfaces of aligned crystallographic structures, using the protein kinase family as a model. Pockets are rapidly computed using two computer programs, FADE and Crevasse. FADE uses gradients of atomic density to locate grooves and pockets on the molecular surface. Crevasse, a new piece of software, splits the FADE output into distinct pockets. The computation was run on 10 kinase catalytic cores aligned on the alphaF-helix, and the resulting pockets spatially clustered. The active site cleft appears as a large, contiguous site that can be subdivided into nucleotide and substrate docking sites. Substrate specificity determinants in the active site cleft between serine/threonine and tyrosine kinases are visible and distinct. The active site clefts cluster tightly, showing a conserved spatial relationship between the active site and alphaF-helix in the C-lobe. When the alphaC-helix is examined, there are multiple mechanisms for anchoring the helix using spatially conserved docking sites. A novel site at the top of the N-lobe is present in all the kinases, and there is a large conserved pocket over the hinge and the alphaC-beta4 loop. Other pockets on the kinase core are strongly conserved but have not yet been mapped to a protein-protein interaction. Sites identified by this algorithm have revealed structural and spatially conserved features of the kinase family and potential conserved intermolecular and intramolecular binding sites.
authors.affiliation: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, 92093, USA.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Thompson
authors.forename: Alexandr P
authors.initials: AP
authors.lastname: Kornev
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Choel
authors.initials: C
authors.lastname: Kim
authors.forename: Lynn F
authors.initials: LF
authors.lastname: Ten Eyck
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
chemical_list: D011494:Protein Kinases