6YTD

CLK1 V324A mutant bound with benzothiazole Tg003 (Cpd 2)

6YTD の概要

• エントリーDOI: 10.2210/pdb6ytd/pdb
• 分子名称: Dual specificity protein kinase CLK1, (1~{Z})-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one (3 entities in total)
• 機能のキーワード: inhibitor, complex, clk1, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39802.79

構造登録者

Schroeder, M.,Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-04-24, 公開日: 2020-07-15, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)