PDBsum entry 5emm

Transferase/transferase inhibitor

PDB id: 5emm

Contents

Protein chains

625 a.a.

313 a.a.

Ligands

SFG

5QL

GOL ×2

Waters ×68

PDB id:

5emm

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of prmt5:mep50 with compound 15 and sinefungin

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. Expression_system_cell_line: sf9. Gene: wdr77, mep50, wd45, hkmt1069, nbla10071.

Resolution:

2.37Å R-factor: 0.237 R-free: 0.293

Authors:

P.A.Boriack-Sjodin,L.Jin

Key ref:

K.W.Duncan et al. (2016). Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett, 7, 162-166. PubMed id: 26985292

Date:

06-Nov-15 Release date: 24-Feb-16

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: 313 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 = SFG) matches with 51.43% similarity)

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

Added reference

ACS Med Chem Lett 7:162-166 (2016)

PubMed id: 26985292

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.

K.W.Duncan, N.Rioux, P.A.Boriack-Sjodin, M.J.Munchhof, L.A.Reiter, C.R.Majer, L.Jin, L.D.Johnston, E.Chan-Penebre, K.G.Kuplast, M.Porter Scott, R.M.Pollock, N.J.Waters, J.J.Smith, M.P.Moyer, R.A.Copeland, R.Chesworth.

ABSTRACT

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).