6YOJ
FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-3,4-dihydro-1H-quinolin-2-one
Summary for 6YOJ
| Entry DOI | 10.2210/pdb6yoj/pdb |
| Descriptor | Focal adhesion kinase 1, 6-[[4-[(3-methylsulfonylphenyl)methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3,4-dihydro-1~{H}-quinolin-2-one (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 | 1 |
| Total formula weight | 32795.71 |
| Authors | Musil, D.,Heinrich, T. (deposition date: 2020-04-14, release date: 2021-02-10, Last modification date: 2024-11-06) |
| 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 Cited by 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: 33497606DOI: 10.1016/j.chembiol.2021.01.003 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.361 Å) |
Structure validation
Download full validation report
