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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: Berger, Benedict-Tilman (Author) , Amaral, Marta (Author) , Kokh, Daria B. (Author) , Nunes-Alves, Ariane (Author) , Musil, Djordje (Author) , Heinrich, Timo (Author) , Schröder, Martin (Author) , Neil, Rebecca (Author) , Wang, Jing (Author) , Navratilova, Iva (Author) , Bomke, Joerg (Author) , Elkins, Jonathan M. (Author) , Müller, Susanne (Author) , Frech, Matthias (Author) , Wade, Rebecca C. (Author) , Knapp, Stefan (Author)
Format: Article (Journal)
Language:English
Published: January 25, 2021
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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Summary: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.
Item Description:Gesehen am 25.05.2021
Physical Description:Online Resource
ISSN:2451-9448
DOI:10.1016/j.chembiol.2021.01.003

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