PDBsum entry 6ckc

Transferase

PDB id: 6ckc

Contents

Protein chains

625 a.a.

303 a.a.

Ligands

F5J

Waters ×68

PDB id:

6ckc

Name:

Transferase

Title:

Structure of prmt5:mep50 in complex with lly-283, a potent and selective inhibitor of prmt5, with antitumor activity

Structure:

Protein arginine n-methyltransferase 5. Chain: a. Synonym: 72 kda icln-binding protein,histone-arginine n- methyltransferase prmt5,jak-binding protein 1,shk1 kinase-binding protein 1 homolog,skb1hs. Engineered: yes. Methylosome protein 50. Chain: b. Synonym: mep-50,androgen receptor cofactor p44,wd repeat-containing

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prmt5, hrmt1l5, ibp72, jbp1, skb1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: wdr77, mep50, wd45, hkmt1069, nbla10071. Expression_system_taxid: 7108

Resolution:

2.80Å R-factor: 0.180 R-free: 0.214

Authors:

S.Antonysamy

Key ref:

Z.Q.Bonday et al. (2018). LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity. ACS Med Chem Lett, 9, 612-617. PubMed id: 30034588

Date:

27-Feb-18 Release date: 16-May-18

Protein chain

O14744  (ANM5_HUMAN) -  Protein arginine N-methyltransferase 5 from Homo sapiens

Seq: 637 a.a.

Struc: 625 a.a.

Protein chain

Q9BQA1  (MEP50_HUMAN) -  Methylosome protein WDR77 from Homo sapiens

Seq: 342 a.a.

Struc: 303 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.2.1.1.320 - type Ii 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 = F5J) matches with 50.00% similarity)

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

Added reference

ACS Med Chem Lett 9:612-617 (2018)

PubMed id: 30034588

LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.

Z.Q.Bonday, G.S.Cortez, M.J.Grogan, S.Antonysamy, K.Weichert, W.P.Bocchinfuso, F.Li, S.Kennedy, B.Li, M.M.Mader, C.H.Arrowsmith, P.J.Brown, M.S.Eram, M.M.Szewczyk, D.Barsyte-Lovejoy, M.Vedadi, E.Guccione, R.M.Campbell.

ABSTRACT

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC₅₀ of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.