4Y30

Crystal structure of human protein arginine methyltransferase PRMT6 bound to SAH and EPZ020411

PDB DOI: https://doi.org/10.2210/pdb4Y30/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2015-02-10 Released: 2015-04-22
Deposition Author(s): Swinger, K.K., Boriack-Sjodin, P.A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.221
R-Value Work: 0.180
R-Value Observed: 0.182

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound.

Mitchell, L.H., Drew, A.E., Ribich, S.A., Rioux, N., Swinger, K.K., Jacques, S.L., Lingaraj, T., Boriack-Sjodin, P.A., Waters, N.J., Wigle, T.J., Moradei, O., Jin, L., Riera, T., Porter-Scott, M., Moyer, M.P., Smith, J.J., Chesworth, R., Copeland, R.A.

(2015) ACS Med Chem Lett 6: 655-659

PubMed: 26101569 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.5b00071
Primary Citation of Related Structures:
4Y2H, 4Y30

PubMed Abstract:
A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies.

Organizational Affiliation

Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02138, United States.

Macromolecule Content

Total Structure Weight: 81 kDa
Atom Count: 6,201
Modelled Residue Count: 688
Deposited Residue Count: 702
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Protein arginine N-methyltransferase 6	A, B	351	Homo sapiens	Mutation(s): 0 Gene Names: PRMT6, HRMT1L6 EC: 2.1.1 (PDB Primary Data), 2.1.1.125 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q96LA8 (Homo sapiens) Explore Q96LA8 Go to UniProtKB: Q96LA8
PHAROS: Q96LA8 GTEx: ENSG00000198890
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q96LA8
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
49L Query on 49L Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain I [auth B] MOL2 format, chain D [auth A] MOL2 format, chain I [auth B]	D [auth A], I [auth B]	N,N'-dimethyl-N-({3-[4-({trans-3-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]cyclobutyl}oxy)phenyl]-1H-pyrazol-4-yl}methyl)ethane-1,2-diamine C₂₅ H₃₈ N₄ O₃ QMDKVNSQXPVCRD-RQNOJGIXSA-N		Interactions Focus chain D [auth A] Focus chain I [auth B] Interactions & Density Focus chain D [auth A] Focus chain I [auth B]
SAH Query on SAH Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B]	C [auth A], H [auth B]	S-ADENOSYL-L-HOMOCYSTEINE C₁₄ H₂₀ N₆ O₅ S ZJUKTBDSGOFHSH-WFMPWKQPSA-N		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth B] SDF format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] MOL2 format, chain F [auth A]	F [auth A], G [auth A], J [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A]	E [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
49L	Binding MOAD: 4Y30	IC50: 10 (nM) from 1 assay(s)
49L	BindingDB: 4Y30	IC50: min: 10, max: 637 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.221
R-Value Work: 0.180
R-Value Observed: 0.182
Space Group: P 4₃

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 99.672	α = 90
b = 99.672	β = 90
c = 89.252	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
HKL-2000	data reduction
PDB_EXTRACT	data extraction
HKL-2000	data scaling
REFMAC	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-04-22

Deposition Author(s):

Swinger, K.K.

Boriack-Sjodin, P.A.

Revision History (Full details and data files)

Version 1.0: 2015-04-22
Type: Initial release
Version 1.1: 2015-07-08
Changes: Database references
Version 1.2: 2024-02-28
Changes: Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy