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| Verfasst von: | Berger, Benedict-Tilman [VerfasserIn]  |
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| | Amaral, Marta [VerfasserIn] |
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| | Kokh, Daria B. [VerfasserIn] |
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| | Nunes-Alves, Ariane [VerfasserIn] |
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| | Musil, Djordje [VerfasserIn] |
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| | Heinrich, Timo [VerfasserIn] |
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| | Schröder, Martin [VerfasserIn] |
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| | Neil, Rebecca [VerfasserIn] |
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| | Wang, Jing [VerfasserIn] |
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| | Navratilova, Iva [VerfasserIn] |
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| | Bomke, Joerg [VerfasserIn] |
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| | Elkins, Jonathan M. [VerfasserIn] |
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| | Müller, Susanne [VerfasserIn] |
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| | Frech, Matthias [VerfasserIn] |
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| | Wade, Rebecca C. [VerfasserIn] |
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| | Knapp, Stefan [VerfasserIn] |
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| Titel: | Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2 |
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| Verf.angabe: | 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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| E-Jahr: | 2021 |
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| Jahr: | January 25, 2021 |
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| Umfang: | 20 S. |
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| Fussnoten: | Gesehen am 25.05.2021 |
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| Titel Quelle: | Enthalten in: Cell chemical biology |
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| Ort Quelle: | Amsterdam : Elsevier, 2016 |
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| Jahr Quelle: | 2021 |
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| Band/Heft Quelle: | 28(2021), 5 vom: Mai, Seite 686-698.e1-e7 |
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| ISSN Quelle: | 2451-9448 |
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| 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. |
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| DOI: | doi:10.1016/j.chembiol.2021.01.003 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1016/j.chembiol.2021.01.003 |
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| | Volltext: http://www.sciencedirect.com/science/article/pii/S2451945621000039 |
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| | DOI: https://doi.org/10.1016/j.chembiol.2021.01.003 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | focal adhesion kinase (FAK) |
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| | kinase inhibitor |
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| | ligand residence time |
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| | NanoBRET |
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| | proline-rich tyrosine kinase 2 (PYK2) |
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| | structure-kinetic-relationship |
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| | τRAMD |
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| K10plus-PPN: | 1745913785 |
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| Verknüpfungen: | → Zeitschrift |
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Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2 / Berger, Benedict-Tilman [VerfasserIn]; January 25, 2021 (Online-Ressource)
