6YVY

FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.

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.

(2021) Cell Chem Biol 28: 686

  • DOI: https://doi.org/10.1016/j.chembiol.2021.01.003
  • Primary Citation of Related Structures:  
    6YOJ, 6YQ1, 6YR9, 6YT6, 6YVS, 6YVY, 6YXV

  • 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.


  • Organizational Affiliation

    Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Focal adhesion kinase 1
A, B, C, D
282Homo sapiensMutation(s): 0 
Gene Names: PTK2FAKFAK1
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q05397 (Homo sapiens)
Explore Q05397 
Go to UniProtKB:  Q05397
PHAROS:  Q05397
GTEx:  ENSG00000169398 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05397
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.974α = 90
b = 75.856β = 102.66
c = 172.64γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted P1EClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-02-10
    Type: Initial release
  • Version 1.1: 2021-06-02
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-10-23
    Changes: Structure summary