PDBsum entry 5e8r

Transferase

PDB id: 5e8r

Contents

Protein chains

332 a.a.

Ligands

SAH ×2

5L6 ×2

UNX ×9

Metals

_CL ×5

Waters ×65

PDB id:

5e8r

Name:

Transferase

Title:

Human hmt1 hnrnp methyltransferase-like protein 6 (s. Cerevisiae)

Structure:

Protein arginine n-methyltransferase 6. Chain: a, b. Synonym: heterogeneous nuclear ribonucleoprotein methyltransferase- like protein 6,histone-arginine n-methyltransferase prmt6. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prmt6, hrmt1l6. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.55Å R-factor: 0.221 R-free: 0.256

Authors:

A.Dong,H.Zeng,J.Liu,W.Tempel,A.Seitova,A.Hutchinson,C.Bountra, C.H.Arrowsmith,A.M.Edwards,J.Jin,P.J.Brown,H.Wu,Structural Genomics Consortium (Sgc)

Key ref:

M.S.Eram et al. (2016). A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases. Acs Chem Biol, 11, 772-781. PubMed id: 26598975 DOI: 10.1021/acschembio.5b00839

Date:

14-Oct-15 Release date: 09-Dec-15

Protein chains

Q96LA8  (ANM6_HUMAN) -  Protein arginine N-methyltransferase 6 from Homo sapiens

Seq: 375 a.a.

Struc: 332 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.1.1.319 - type I protein arginine methyltransferase.
• Reaction: L-arginyl-[protein] + 2 S-adenosyl-L-methionine = N(omega),N(omega)- dimethyl-L-arginyl-[protein] + 2 S-adenosyl-L-homocysteine + 2 H⁺

L-arginyl-[protein] + 2 × S-adenosyl-L-methionine = N(omega),N(omega)- dimethyl-L-arginyl-[protein] + 2 × S-adenosyl-L-homocysteine + 2 × H(+) (Bound ligand (Het Group name = SAH) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acschembio.5b00839

Acs Chem Biol 11:772-781 (2016)

PubMed id: 26598975

A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases.

M.S.Eram, Y.Shen, M.M.Szewczyk, H.Wu, G.Senisterra, F.Li, K.V.Butler, H.Ã.œ.Kaniskan, B.A.Speed, C.dela Seña, A.Dong, H.Zeng, M.Schapira, P.J.Brown, C.H.Arrowsmith, D.Barsyte-Lovejoy, J.Liu, M.Vedadi, J.Jin.

ABSTRACT

Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.