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8BN8

METTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM3006

This is a non-PDB format compatible entry.
Summary for 8BN8
Entry DOI10.2210/pdb8bn8/pdb
DescriptorN6-adenosine-methyltransferase catalytic subunit, N6-adenosine-methyltransferase non-catalytic subunit, 2-[[4-(6-bromanyl-2~{H}-indazol-4-yl)-1,2,3-triazol-1-yl]methyl]-6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridine, ... (4 entities in total)
Functional Keywordsmethyltransferase, sam, inhibitor, m6a, rna binding protein
Biological sourceHomo sapiens (human)
More
Total number of polymer chains2
Total formula weight59211.40
Authors
Pilka, E.S.,Thomas, B.,Blackaby, W.,Hardick, D.,Feeney, K.,Ridgill, M.,Rotty, B.,Rausch, O. (deposition date: 2022-11-13, release date: 2023-09-20, Last modification date: 2024-11-06)
Primary citationGuirguis, A.A.,Ofir-Rosenfeld, Y.,Knezevic, K.,Blackaby, W.,Hardick, D.,Chan, Y.C.,Motazedian, A.,Gillespie, A.,Vassiliadis, D.,Lam, E.Y.N.,Tran, K.,Andrews, B.,Harbour, M.E.,Vasiliauskaite, L.,Saunders, C.J.,Tsagkogeorga, G.,Azevedo, A.,Obacz, J.,Pilka, E.S.,Carkill, M.,MacPherson, L.,Wainwright, E.N.,Liddicoat, B.,Blyth, B.J.,Albertella, M.R.,Rausch, O.,Dawson, M.A.
Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity.
Cancer Discov, 13:2228-2247, 2023
Cited by
PubMed Abstract: Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti-PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole-cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.
PubMed: 37548590
DOI: 10.1158/2159-8290.CD-23-0007
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.213 Å)
Structure validation

238268

数据于2025-07-02公开中

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