Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
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...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 25, 2021
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| In: |
Cell chemical biology
Year: 2021, Volume: 28, Issue: 5, Pages: 686-698.e1-e7 |
| ISSN: | 2451-9448 |
| DOI: | 10.1016/j.chembiol.2021.01.003 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.chembiol.2021.01.003 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2451945621000039 
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| Author Notes: | Benedict-Tilman Berger, Marta Amaral, Daria B. Kokh, Ariane Nunes-Alves, Djordje Musil, Timo Heinrich, Martin Schröder, Rebecca Neil, Jing Wang, Iva Navratilova, Joerg Bomke, Jonathan M. Elkins, Susanne Müller, Matthias Frech, Rebecca C. Wade, Stefan Knapp |
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| 245 | 1 | 0 | |a Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2 |c Benedict-Tilman Berger, Marta Amaral, Daria B. Kokh, Ariane Nunes-Alves, Djordje Musil, Timo Heinrich, Martin Schröder, Rebecca Neil, Jing Wang, Iva Navratilova, Joerg Bomke, Jonathan M. Elkins, Susanne Müller, Matthias Frech, Rebecca C. Wade, Stefan Knapp |
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| 520 | |a 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. | ||
| 650 | 4 | |a focal adhesion kinase (FAK) | |
| 650 | 4 | |a kinase inhibitor | |
| 650 | 4 | |a ligand residence time | |
| 650 | 4 | |a NanoBRET | |
| 650 | 4 | |a proline-rich tyrosine kinase 2 (PYK2) | |
| 650 | 4 | |a structure-kinetic-relationship | |
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