Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.
Cell Chem Biol
; 28(5): 686-698.e7, 2021 05 20.
Article
in En
| MEDLINE
| ID: mdl-33497606
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sulfonamides
/
Protein Kinase Inhibitors
/
Focal Adhesion Kinase 1
/
Indoles
Limits:
Female
/
Humans
Language:
En
Journal:
Cell Chem Biol
Year:
2021
Document type:
Article
Country of publication:
United States