8vlh | pdb_00008vlh

Crystal structure of Ash1L PHD-BAH domains

spinqualitylabelsall models 8vlh, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8vlh is a 2 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 2.403Å Ligands: SR, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ASH1L_HUMAN Histone methyltransferase specifically methylating 'Lys-36' of histone H3 (H3K36me). Publication Abstract from PubMed The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1L(BD)), a plant homeodomain (ASH1L(PHD)) finger, and a bromo-adjacent homology (ASH1L(BAH)) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1L(PHD) recognizes H3K4me2/3, whereas the neighboring ASH1L(BD) and ASH1L(BAH) have DNA binding activities. The DNA binding function of ASH1L(BAH) is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1L(PHD) stabilizes the ASH1L(BAH) fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1L(PHD) with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L. Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation.,Vann KR, Sharma R, Hsu CC, Devoucoux M, Tencer AH, Zeng L, Lin K, Zhu L, Li Q, Lachance C, Ospina RR, Tong Q, Cheung KL, Yang S, Biswas S, Xuan H, Gatchalian J, Alamillo L, Wang J, Jang SM, Klein BJ, Lu Y, Ernst P, Strahl BD, Rothbart SB, Walsh MJ, Cleary ML, Cote J, Shi X, Zhou MM, Kutateladze TG Nat Commun. 2025 Mar 6;16(1):2235. doi: 10.1038/s41467-025-57556-5. PMID:40044670 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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