B-Raf Kinase V600E oncogenic mutant in complex with PLX4032

Experimental Data Snapshot

  • Resolution: 2.45 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

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Ligand Structure Quality Assessment 

This is version 1.4 of the entry. See complete history


Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.

Bollag, G.Hirth, P.Tsai, J.Zhang, J.Ibrahim, P.N.Cho, H.Spevak, W.Zhang, C.Zhang, Y.Habets, G.Burton, E.A.Wong, B.Tsang, G.West, B.L.Powell, B.Shellooe, R.Marimuthu, A.Nguyen, H.Zhang, K.Y.Artis, D.R.Schlessinger, J.Su, F.Higgins, B.Iyer, R.D'Andrea, K.Koehler, A.Stumm, M.Lin, P.S.Lee, R.J.Grippo, J.Puzanov, I.Kim, K.B.Ribas, A.McArthur, G.A.Sosman, J.A.Chapman, P.B.Flaherty, K.T.Xu, X.Nathanson, K.L.Nolop, K.

(2010) Nature 467: 596-599

  • DOI: https://doi.org/10.1038/nature09454
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 

    B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

  • Organizational Affiliation

    Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA. gbollag@plexxikon.com

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
AKAP9-BRAF fusion protein
A, B
289Homo sapiensMutation(s): 16 
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
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Query on 032

Download Ideal Coordinates CCD File 
C [auth A]N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide
C23 H18 Cl F2 N3 O3 S
Binding Affinity Annotations 
IDSourceBinding Affinity
032 BindingDB:  3OG7 Kd: min: 51, max: 58 (nM) from 2 assay(s)
IC50: min: 4, max: 3.30e+4 (nM) from 30 assay(s)
EC50: min: 601, max: 2290 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Resolution: 2.45 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.77α = 90
b = 104.424β = 90
c = 110.128γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Structure summary
  • Version 1.3: 2018-05-02
    Changes: Data collection, Structure summary
  • Version 1.4: 2024-02-21
    Changes: Data collection, Database references, Derived calculations, Structure summary