5FA5

Crystal Structure of PRMT5:MEP50 in complex with MTA and H4 peptide

5FA5 の概要

• エントリーDOI: 10.2210/pdb5fa5/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, Histone H4, ... (5 entities in total)
• 機能のキーワード: methyl transferase, transferase-protein binding complex, transferase/protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm : O14744; Nucleus: Q9BQA1 P62805
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 116437.45

構造登録者

Sprague, E.R.,McNamara, J.T. (登録日: 2015-12-10, 公開日: 2016-02-24, 最終更新日: 2023-09-27)

主引用文献

Mavrakis, K.J.,McDonald, E.R.,Schlabach, M.R.,Billy, E.,Hoffman, G.R.,deWeck, A.,Ruddy, D.A.,Venkatesan, K.,Yu, J.,McAllister, G.,Stump, M.,deBeaumont, R.,Ho, S.,Yue, Y.,Liu, Y.,Yan-Neale, Y.,Yang, G.,Lin, F.,Yin, H.,Gao, H.,Kipp, D.R.,Zhao, S.,McNamara, J.T.,Sprague, E.R.,Zheng, B.,Lin, Y.,Cho, Y.S.,Gu, J.,Crawford, K.,Ciccone, D.,Vitari, A.C.,Lai, A.,Capka, V.,Hurov, K.,Porter, J.A.,Tallarico, J.,Mickanin, C.,Lees, E.,Pagliarini, R.,Keen, N.,Schmelzle, T.,Hofmann, F.,Stegmeier, F.,Sellers, W.R.
Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.
Science, 351:1208-1213, 2016

PubMed 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.

PubMed: 26912361
DOI: 10.1126/science.aad5944

実験手法

X-RAY DIFFRACTION (2.34 Å)