6YU1

CLK3 bound with beta-carboline KH-CARB13 (Cpd 3)

Summary for 6YU1

• Entry DOI: 10.2210/pdb6yu1/pdb
• Descriptor: Dual specificity protein kinase CLK3, 1,2-ETHANEDIOL, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, clk3, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 87402.17

Authors

Schroeder, M.,Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-04-25, release date: 2020-07-15, Last modification date: 2024-01-24)

Primary citation

Schroder, M.,Bullock, A.N.,Fedorov, O.,Bracher, F.,Chaikuad, A.,Knapp, S.
DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity.
J.Med.Chem., 63:10224-10234, 2020

PubMed Abstract: Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

PubMed: 32787076
DOI: 10.1021/acs.jmedchem.0c00898

Experimental method

X-RAY DIFFRACTION (1.9 Å)