6YR9

FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide

Summary for 6YR9

• Entry DOI: 10.2210/pdb6yr9/pdb
• Descriptor: Focal adhesion kinase 1, N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide (3 entities in total)
• Functional Keywords: protein tyrosine kinase, atp binding, transferase, transferase-inhibitor complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 131234.82

Authors

Musil, D.,Amaral, M. (deposition date: 2020-04-19, release date: 2021-02-10, Last modification date: 2024-11-13)

Primary citation

Berger, B.T.,Amaral, M.,Kokh, D.B.,Nunes-Alves, A.,Musil, D.,Heinrich, T.,Schroder, M.,Neil, R.,Wang, J.,Navratilova, I.,Bomke, J.,Elkins, J.M.,Muller, S.,Frech, M.,Wade, R.C.,Knapp, S.
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.
Cell Chem Biol, 28:686-, 2021

PubMed Abstract: 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.

PubMed: 33497606
DOI: 10.1016/j.chembiol.2021.01.003

Experimental method

X-RAY DIFFRACTION (1.925 Å)