Cover Image

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...

Full description

Saved in:
Bibliographic Details
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
Get full text
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

MARC

LEADER 00000caa a2200000 c 4500
001 1745913785
003 DE-627
005 20230426075021.0
007 cr uuu---uuuuu
008 210128s2021 xx |||||o 00| ||eng c
024 7 |a 10.1016/j.chembiol.2021.01.003  |2 doi 
035 |a (DE-627)1745913785 
035 |a (DE-599)KXP1745913785 
035 |a (OCoLC)1341389858 
040 |a DE-627  |b ger  |c DE-627  |e rda 
041 |a eng 
084 |a 32  |2 sdnb 
100 1 |a Berger, Benedict-Tilman  |d 1991-  |e VerfasserIn  |0 (DE-588)1220051454  |0 (DE-627)1736233785  |4 aut 
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 
264 1 |c January 25, 2021 
300 |a 20 
336 |a Text  |b txt  |2 rdacontent 
337 |a Computermedien  |b c  |2 rdamedia 
338 |a Online-Ressource  |b cr  |2 rdacarrier 
500 |a Gesehen am 25.05.2021 
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 
650 4 |a τRAMD 
700 1 |a Amaral, Marta  |e VerfasserIn  |4 aut 
700 1 |a Kokh, Daria B.  |e VerfasserIn  |0 (DE-588)1150707844  |0 (DE-627)1010913387  |0 (DE-576)497188945  |4 aut 
700 1 |a Nunes-Alves, Ariane  |e VerfasserIn  |4 aut 
700 1 |a Musil, Djordje  |e VerfasserIn  |4 aut 
700 1 |a Heinrich, Timo  |e VerfasserIn  |4 aut 
700 1 |a Schröder, Martin  |e VerfasserIn  |4 aut 
700 1 |a Neil, Rebecca  |e VerfasserIn  |4 aut 
700 1 |a Wang, Jing  |e VerfasserIn  |4 aut 
700 1 |a Navratilova, Iva  |e VerfasserIn  |4 aut 
700 1 |a Bomke, Joerg  |e VerfasserIn  |4 aut 
700 1 |a Elkins, Jonathan M.  |e VerfasserIn  |4 aut 
700 1 |a Müller, Susanne  |e VerfasserIn  |4 aut 
700 1 |a Frech, Matthias  |e VerfasserIn  |4 aut 
700 1 |a Wade, Rebecca C.  |e VerfasserIn  |0 (DE-588)102801774X  |0 (DE-627)730136000  |0 (DE-576)276591402  |4 aut 
700 1 |a Knapp, Stefan  |e VerfasserIn  |4 aut 
773 0 8 |i Enthalten in  |t Cell chemical biology  |d Amsterdam : Elsevier, 2016  |g 28(2021), 5 vom: Mai, Seite 686-698.e1-e7  |h Online-Ressource  |w (DE-627)85381872X  |w (DE-600)2850144-5  |w (DE-576)462624013  |x 2451-9448  |7 nnas  |a Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2 
773 1 8 |g volume:28  |g year:2021  |g number:5  |g month:05  |g pages:686-698.e1-e7  |g extent:20  |a Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2 
856 4 0 |u https://doi.org/10.1016/j.chembiol.2021.01.003  |x Verlag  |x Resolving-System  |z lizenzpflichtig  |3 Volltext 
856 4 0 |u http://www.sciencedirect.com/science/article/pii/S2451945621000039  |x Verlag  |z lizenzpflichtig  |3 Volltext 
951 |a AR 
992 |a 20210128 
993 |a Article 
994 |a 2021 
998 |g 102801774X  |a Wade, Rebecca C.  |m 102801774X:Wade, Rebecca C.  |d 140000  |e 140000PW102801774X  |k 0/140000/  |p 15 
998 |g 1150707844  |a Kokh, Daria B.  |m 1150707844:Kokh, Daria B.  |p 3 
999 |a KXP-PPN1745913785  |e 3843693560 
BIB |a Y 
SER |a journal 
JSO |a {"name":{"displayForm":["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"]},"title":[{"title_sort":"Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2","title":"Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2"}],"recId":"1745913785","physDesc":[{"extent":"20 S."}],"relHost":[{"type":{"bibl":"periodical","media":"Online-Ressource"},"pubHistory":["Volume 23, number 1 (January 21, 2016)-"],"note":["Gesehen am 01.03.2022"],"title":[{"title_sort":"Cell chemical biology","title":"Cell chemical biology"}],"disp":"Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2Cell chemical biology","recId":"85381872X","physDesc":[{"extent":"Online-Ressource"}],"part":{"text":"28(2021), 5 vom: Mai, Seite 686-698.e1-e7","year":"2021","volume":"28","extent":"20","pages":"686-698.e1-e7","issue":"5"},"id":{"zdb":["2850144-5"],"issn":["2451-9448"],"eki":["85381872X"]},"origin":[{"publisher":"Elsevier","dateIssuedDisp":"[2016]-","publisherPlace":"Amsterdam"}],"language":["eng"]}],"id":{"doi":["10.1016/j.chembiol.2021.01.003"],"eki":["1745913785"]},"origin":[{"dateIssuedKey":"2021","dateIssuedDisp":"January 25, 2021"}],"language":["eng"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"note":["Gesehen am 25.05.2021"],"person":[{"roleDisplay":"VerfasserIn","family":"Berger","role":"aut","given":"Benedict-Tilman","display":"Berger, Benedict-Tilman"},{"family":"Amaral","roleDisplay":"VerfasserIn","role":"aut","given":"Marta","display":"Amaral, Marta"},{"display":"Kokh, Daria B.","given":"Daria B.","role":"aut","family":"Kokh","roleDisplay":"VerfasserIn"},{"given":"Ariane","display":"Nunes-Alves, Ariane","family":"Nunes-Alves","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","family":"Musil","roleDisplay":"VerfasserIn","display":"Musil, Djordje","given":"Djordje"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Heinrich","display":"Heinrich, Timo","given":"Timo"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Schröder","display":"Schröder, Martin","given":"Martin"},{"given":"Rebecca","display":"Neil, Rebecca","family":"Neil","roleDisplay":"VerfasserIn","role":"aut"},{"roleDisplay":"VerfasserIn","family":"Wang","role":"aut","given":"Jing","display":"Wang, Jing"},{"display":"Navratilova, Iva","given":"Iva","role":"aut","family":"Navratilova","roleDisplay":"VerfasserIn"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Bomke","display":"Bomke, Joerg","given":"Joerg"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Elkins","display":"Elkins, Jonathan M.","given":"Jonathan M."},{"display":"Müller, Susanne","given":"Susanne","role":"aut","roleDisplay":"VerfasserIn","family":"Müller"},{"roleDisplay":"VerfasserIn","family":"Frech","role":"aut","given":"Matthias","display":"Frech, Matthias"},{"role":"aut","family":"Wade","roleDisplay":"VerfasserIn","display":"Wade, Rebecca C.","given":"Rebecca C."},{"family":"Knapp","roleDisplay":"VerfasserIn","role":"aut","given":"Stefan","display":"Knapp, Stefan"}]} 
SRT |a BERGERBENESTRUCTUREK2520 

Similar Items