6nt2

type 1 PRMT in complex with the inhibitor GSK3368715

spinqualitylabelsall models 6nt2, resolution 2.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nt2 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.48Å Ligands: DTT, GOL, KZS, SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ANM1_HUMAN Arginine methyltransferase that methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, ILF3, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15, EWS, HABP4 and SERBP1 (PubMed:10749851, PubMed:16879614, PubMed:26876602). Constitutes the main enzyme that mediates monomethylation and asymmetric dimethylation of histone H4 'Arg-4' (H4R3me1 and H4R3me2a, respectively), a specific tag for epigenetic transcriptional activation. May be involved in the regulation of TAF15 transcriptional activity, act as an activator of estrogen receptor (ER)-mediated transactivation, play a key role in neurite outgrowth and act as a negative regulator of megakaryocytic differentiation, by modulating p38 MAPK pathway. Methylates RBM15, promoting ubiquitination and degradation of RBM15 (PubMed:26575292). Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity. Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity (PubMed:25284789). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). Publication Abstract from PubMed Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection. Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.,Fedoriw A, Rajapurkar SR, O'Brien S, Gerhart SV, Mitchell LH, Adams ND, Rioux N, Lingaraj T, Ribich SA, Pappalardi MB, Shah N, Laraio J, Liu Y, Butticello M, Carpenter CL, Creasy C, Korenchuk S, McCabe MT, McHugh CF, Nagarajan R, Wagner C, Zappacosta F, Annan R, Concha NO, Thomas RA, Hart TK, Smith JJ, Copeland RA, Moyer MP, Campbell J, Stickland K, Mills J, Jacques-O'Hagan S, Allain C, Johnston D, Raimondi A, Porter Scott M, Waters N, Swinger K, Boriack-Sjodin A, Riera T, Shapiro G, Chesworth R, Prinjha RK, Kruger RG, Barbash O, Mohammad HP Cancer Cell. 2019 Jul 8;36(1):100-114.e25. doi: 10.1016/j.ccell.2019.05.014. Epub, 2019 Jun 27. PMID:31257072 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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