Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.chembiol.2021.01.003

Type

Journal article

Journal

Cell Chem Biol

Publication Date

20/05/2021

Volume

28

Pages

686 - 698.e7

Keywords

NanoBRET, focal adhesion kinase (FAK), kinase inhibitor, ligand residence time, proline-rich tyrosine kinase 2 (PYK2), structure-kinetic-relationship, τRAMD, Cells, Cultured, Female, Focal Adhesion Kinase 1, HEK293 Cells, Humans, Indoles, Kinetics, Ligands, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Sulfonamides