PDBsum entry 5fa5

Transferase/protein binding

PDB id: 5fa5

Contents

Protein chains

625 a.a.

301 a.a.

Ligands

ARG

MTA

Waters ×168

PDB id:

5fa5

Name:

Transferase/protein binding

Title:

Crystal structure of prmt5:mep50 in complex with mta and h4 peptide

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. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.34Å R-factor: 0.179 R-free: 0.221

Authors:

E.R.Sprague,J.T.Mcnamara

Key ref:

K.J.Mavrakis et al. (2016). Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science, 351, 1208-1213. PubMed id: 26912361 DOI: 10.1126/science.aad5944

Date:

10-Dec-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: 301 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 = MTA) matches with 76.92% similarity)

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

Added reference

DOI no: 10.1126/science.aad5944

Science 351:1208-1213 (2016)

PubMed id: 26912361

Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.

K.J.Mavrakis, E.R.McDonald, M.R.Schlabach, E.Billy, G.R.Hoffman, A.deWeck, D.A.Ruddy, K.Venkatesan, J.Yu, G.McAllister, M.Stump, R.deBeaumont, S.Ho, Y.Yue, Y.Liu, Y.Yan-Neale, G.Yang, F.Lin, H.Yin, H.Gao, D.R.Kipp, S.Zhao, J.T.McNamara, E.R.Sprague, B.Zheng, Y.Lin, Y.S.Cho, J.Gu, K.Crawford, D.Ciccone, A.C.Vitari, A.Lai, V.Capka, K.Hurov, J.A.Porter, J.Tallarico, C.Mickanin, E.Lees, R.Pagliarini, N.Keen, T.Schmelzle, F.Hofmann, F.Stegmeier, W.R.Sellers.

ABSTRACT

5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.