6ARV

Crystal structure of CARM1 with Compound 2 and SAH


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

Drew, A.E.Moradei, O.Jacques, S.L.Rioux, N.Boriack-Sjodin, A.P.Allain, C.Scott, M.P.Jin, L.Raimondi, A.Handler, J.L.Ott, H.M.Kruger, R.G.McCabe, M.T.Sneeringer, C.Riera, T.Shapiro, G.Waters, N.J.Mitchell, L.H.Duncan, K.W.Moyer, M.P.Copeland, R.A.Smith, J.Chesworth, R.Ribich, S.A.

(2017) Sci Rep 7: 17993-17993

  • DOI: https://doi.org/10.1038/s41598-017-18446-z
  • Primary Citation of Related Structures:  
    6ARJ, 6ARV

  • PubMed Abstract: 

    CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC 50  = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC 50 values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases.


  • Organizational Affiliation

    Epizyme, Inc., Cambridge, Massachusetts, USA. adrew@epizyme.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-arginine methyltransferase CARM1
A, B, C, D
349Homo sapiensMutation(s): 0 
Gene Names: CARM1PRMT4
EC: 2.1.1.319
UniProt & NIH Common Fund Data Resources
Find proteins for Q86X55 (Homo sapiens)
Explore Q86X55 
Go to UniProtKB:  Q86X55
PHAROS:  Q86X55
GTEx:  ENSG00000142453 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86X55
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BW7
Query on BW7

Download Ideal Coordinates CCD File 
F [auth A],
L [auth B],
P [auth C],
T [auth D]
(2R)-1-amino-3-{3-[4-(morpholin-4-yl)-1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]phenoxy}propan-2-ol
C22 H29 N5 O3
CPPUUUMUDLYZRX-QGZVFWFLSA-N
SAH
Query on SAH

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B],
O [auth C],
S [auth D]
S-ADENOSYL-L-HOMOCYSTEINE
C14 H20 N6 O5 S
ZJUKTBDSGOFHSH-WFMPWKQPSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
J [auth A]
M [auth B]
G [auth A],
H [auth A],
I [auth A],
J [auth A],
M [auth B],
N [auth B],
Q [auth C],
R [auth C],
U [auth D],
V [auth D],
W [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SAH BindingDB:  6ARV Ki: min: 400, max: 860 (nM) from 2 assay(s)
BW7 Binding MOAD:  6ARV IC50: 46 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.23α = 90
b = 99.12β = 90
c = 208.85γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Data collection, Database references