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

Abstract

The active form of kinases is shared across different family members, as are several commonly observed inactive forms. We previously performed a clustering of the conformation of the activation loop of all protein kinase structures in the Protein Data Bank (PDB) into eight classes based on the dihedral angles that place the Phe side chain of the DFG motif at the N-terminus of the activation loop. Our clusters are strongly associated with the placement of the activation loop, the C-helix, and other structural elements of kinases. We present Kincore, a web resource providing access to our conformational assignments for kinase structures in the PDB. While other available databases provide conformational states or drug type but not both, KinCore includes the conformational state and the inhibitor type (Type 1, 1.5, 2, 3, allosteric) for each kinase chain. The user can query and browse the database using these attributes or determine the conformational labels of a kinase structure using the web server or a standalone program. The database and labeled structure files can be downloaded from the server. Kincore will help in understanding the conformational dynamics of these proteins and guide development of inhibitors targeting specific states. Kincore is available at http://dunbrack.fccc.edu/kincore.

Figure 1.

Representative protein kinase structure (3ETA_A) displaying the residues used to define inhibitor binding regions.

Figure 2.

Screenshot of database table displaying entries for PDB chains of CDK2. Every blue string is clickable and will open up a new window with data on all chains corresponding to the link, including the PDB entry (clicking on a chain will lead to a page describing the whole entry), the spatial label (e.g. DFGin), the dihedral label (e.g. BLBplus), the ligand (e.g. ‘STU’) and the type of inhibitor (e.g. Type1). Each page provides links to a tab-separated file with the data from the page and to PyMOL sessions and mmCIF coordinate files for all chains listed on the page.

Figure 3.

Images of kinase structures that result from searches and downloads from Kincore. (A) BRAF DFGin-BLBplus structures (‘SRC-inactive’ conformation in blue with grayish-blue activation loop) compared with DFGin-BLAminus (orange, active conformations), BLBminus (cyan-light cyan), DFGin-BLAplus (‘FGFR-inactive’, forest green-light green) and DFGout-BBAminus (Type-2 ligand binding, light brown-yellow). A small number of outlier structures in some classes are not shown. (B) EGFR BLAminus (107 chains, left, orange) and BLBplus (79 chains, right, blue) structures with both the activation loop (right side of each image) and C-terminal tail (left side of each image) shown in lighter colors. The C-terminus of each group is shown in magenta spheres. (C) ATP-bound BLAminus structures from 14 different kinases in 6 kinase families (left) and BBAminus structures from 29 kinases with bound Type 2 inhibitors (right).