Kincore: a web resource for structural classification of protein kinases and their inhibitors

Abstract

Protein kinases exhibit significant structural diversity, primarily in the conformation of the activation loop and other components of the active site. We previously performed a clustering of the conformation of the activation loop of all protein kinase structures in the Protein Data Bank (Modi and Dunbrack, PNAS, 116:6818-6827, 2019) into 8 classes based on the location of the Phe side chain of the DFG motif at the N-terminus of the activation loop. This is determined with a distance metric that measures the difference in the dihedral angles that determine the placement of the Phe side chains (the ϕ, ψ of X, D, and F of the X-DFG motif and the χ1 of the Phe side chain). The nomenclature is based on the regions of the Ramachandran map occupied by the XDF residues and the χ1 rotamer of the Phe residue. All active structures are “BLAminus”, while common inactive DFGin conformations are “BLBplus” and “ABAminus”. Type II inhibitors bind almost exclusively to the DFGout “BBAminus” conformation. In this paper, we present Kincore (http://dunbrack.fccc.edu/kincore), a web resource providing access to the conformational assignments based on our clustering along with labels for ligand types (Type I, Type II, etc.) bound to each kinase chain in the PDB. The data are annotated with several properties including PDBid, Uniprotid, gene, protein name, phylogenetic group, spatial and dihedral labels for orientation of DFGmotif residues, C-helix disposition, ligand name and type. The user can browse and query the database using these attributes individually or perform advanced search using a combination of them like a phylogenetic group with specific conformational label and ligand type. The user can also determine the spatial and dihedral labels for a structure with unknown conformation using the web server and standalone program. The entire database can be downloaded as text files and structure files in PyMOL sessions and mmCIF format. We believe that Kincore will help in understanding conformational dynamics of these proteins and guide development of inhibitors targeting specific states.

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

“…3A) (31). There are excellent online resources available to explore the conformational diversity of protein kinases and kinase-inhibitors complexes, notably KINCORE and KLIFS (35,36).…”

Conformational changes in the essentialE. coliseptal cell wall synthesis complex suggest an activation mechanism

“…Structure prediction was also recently applied to other divisome interactions 19,23 . While AF2 makes predictions that are largely consistent with available structural data and can accurately predict protein-protein interfaces 24-26 , its predictions can fail to distinguish between different states of the same complex 27 or describe the consequences of point mutations 28 .…”

KiSSim: Predicting Off-Targets from Structural Similarities in the Kinome

“…The recent breakthrough of AlphaFold2 could help here; predicted structures for almost all human kinases are available now on the AlphaFold DB . Modi and Dunbrack have already classified the structures’ conformations and found most structures in the DFG-in conformation. An AlphaFold-enhanced KiSSim tree may further increase the usefulness of the KiSSim methodology for kinome-wide similarity studies.…”