4JVG

B-Raf Kinase in Complex with Birb796


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.09 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.235 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.

Lavoie, H.Thevakumaran, N.Gavory, G.Li, J.J.Padeganeh, A.Guiral, S.Duchaine, J.Mao, D.Y.Bouvier, M.Sicheri, F.Therrien, M.

(2013) Nat Chem Biol 9: 428-436

  • DOI: https://doi.org/10.1038/nchembio.1257
  • Primary Citation of Related Structures:  
    4JVG

  • PubMed Abstract: 

    RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain.


  • Organizational Affiliation

    Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signalling, Université de Montréal, Montréal, Québec, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase B-rafA [auth B],
B [auth A],
C,
D
284Homo sapiensMutation(s): 16 
Gene Names: BRAFBRAF1RAFB1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P15056 (Homo sapiens)
Explore P15056 
Go to UniProtKB:  P15056
PHAROS:  P15056
GTEx:  ENSG00000157764 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15056
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
B96 BindingDB:  4JVG Kd: min: 27, max: 1.00e+4 (nM) from 3 assay(s)
IC50: 83.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.09 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.235 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.997α = 90
b = 120.61β = 90.44
c = 81.714γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-29
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations