5U4X

Coactivator-associated arginine methyltransferase 1 with TP-064


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma.

Nakayama, K.Szewczyk, M.M.Dela Sena, C.Wu, H.Dong, A.Zeng, H.Li, F.de Freitas, R.F.Eram, M.S.Schapira, M.Baba, Y.Kunitomo, M.Cary, D.R.Tawada, M.Ohashi, A.Imaeda, Y.Saikatendu, K.S.Grimshaw, C.E.Vedadi, M.Arrowsmith, C.H.Barsyte-Lovejoy, D.Kiba, A.Tomita, D.Brown, P.J.

(2018) Oncotarget 9: 18480-18493

  • DOI: https://doi.org/10.18632/oncotarget.24883
  • Primary Citation of Related Structures:  
    5U4X

  • PubMed Abstract: 

    Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC 50 < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC 50 = 340 ± 30 nM) and Mediator complex subunit 12 (MED12; IC 50 = 43 ± 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition.


  • Organizational Affiliation

    Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-arginine methyltransferase CARM1
A, B, C, D
341Homo 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
7VM
Query on 7VM

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
Q [auth C],
W [auth D]
N-methyl-N-[(2-{1-[2-(methylamino)ethyl]piperidin-4-yl}pyridin-4-yl)methyl]-3-phenoxybenzamide
C28 H34 N4 O2
VUIITYLFSAXKIQ-UHFFFAOYSA-N
SAH
Query on SAH

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

Download Ideal Coordinates CCD File 
AA [auth D]
BA [auth D]
CA [auth D]
DA [auth D]
G [auth A]
AA [auth D],
BA [auth D],
CA [auth D],
DA [auth D],
G [auth A],
H [auth A],
K [auth B],
L [auth B],
M [auth B],
N [auth B],
O [auth B],
R [auth C],
S [auth C],
T [auth C],
U [auth C],
X [auth D],
Y [auth D],
Z [auth D]
UNKNOWN ATOM OR ION
X
Binding Affinity Annotations 
IDSourceBinding Affinity
SAH BindingDB:  5U4X Ki: min: 400, max: 860 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.091α = 90
b = 98.919β = 90
c = 207.553γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-21
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Structure summary
  • Version 1.2: 2018-05-23
    Changes: Data collection, Database references
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description