Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Journal article

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.

Authors: Berger, B-T; Amaral, M; Kokh, DB; Nunes-Alves, A; Musil, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Chemical Biology
• Volume: 28
• Issue: 5
• Pages: 686-698.E7
• Publication date: 2021-01-25
• Acceptance date: 2021-01-04
• DOI: 10.1016/j.chembiol.2021.01.003
• EISSN: 2451-9448
• ISSN: 2451-9456
• Pmid: 33497606
• Language: English
• Keywords: focal adhesion kinase (FAK); kinase inhibitor; NanoBRET; FFR; structure-kinetic-relationship; proline-rich tyrosine kinase 2 (PYK2); ligand residence time; τRAMD