DFG-1 residue controls inhibitor binding mode and affinity, providing a basis for rational design of kinase inhibitor selectivity

  • 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.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Author:Martin SchröderORCiDGND, Alex N. BullockORCiD, Oleg Fedorov, Franz BracherORCiDGND, Apirat ChaikuadORCiD, Stefan KnappORCiD
Parent Title (English):Journal of Medicinal Chemistry
Publisher:American Chemical Society
Place of publication:Washington, DC
Document Type:Article
Date of Publication (online):2020/08/12
Date of first Publication:2020/08/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/08/06
Page Number:11
First Page:10224
Last Page:10234
Institutes:Biochemie, Chemie und Pharmazie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0