5C9C

CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.

Peng, S.B.Henry, J.R.Kaufman, M.D.Lu, W.P.Smith, B.D.Vogeti, S.Rutkoski, T.J.Wise, S.Chun, L.Zhang, Y.Van Horn, R.D.Yin, T.Zhang, X.Yadav, V.Chen, S.H.Gong, X.Ma, X.Webster, Y.Buchanan, S.Mochalkin, I.Huber, L.Kays, L.Donoho, G.P.Walgren, J.McCann, D.Patel, P.Conti, I.Plowman, G.D.Starling, J.J.Flynn, D.L.

(2015) Cancer Cell 28: 384-398

  • DOI: https://doi.org/10.1016/j.ccell.2015.08.002
  • Primary Citation of Related Structures:  
    5C9C

  • PubMed Abstract: 

    LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.


  • Organizational Affiliation

    Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: peng_sheng-bin@lilly.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase B-raf
A, B
307Homo sapiensMutation(s): 1 
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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4Z5
Query on 4Z5

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-(3,3-dimethylbutyl)-3-{2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl}urea
C23 H29 F N6 O
HHCBMISMPSAZBF-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth B]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
4Z5 BindingDB:  5C9C Ki: 0.14 (nM) from 1 assay(s)
IC50: min: 1.5, max: 5800 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.88α = 90
b = 93.88β = 90
c = 165.55γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACrefinement
Cootmodel building
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-15
    Type: Initial release
  • Version 1.1: 2015-10-14
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description