6WXK

PHF23 PHD Domain Apo

Summary for 6WXK

• Entry DOI: 10.2210/pdb6wxk/pdb
• Descriptor: PHD finger protein 23, ZINC ION (2 entities in total)
• Functional Keywords: phf23, phd finger, histone, chromatin, nup98 fusion, metal binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 35620.79

Authors

Vann, K.R.,Zhang, J.,Zhang, Y.,Kutateladze, T. (deposition date: 2020-05-11, release date: 2020-07-15, Last modification date: 2024-10-23)

Primary citation

Zhang, Y.,Guo, Y.,Gough, S.M.,Zhang, J.,Vann, K.R.,Li, K.,Cai, L.,Shi, X.,Aplan, P.D.,Wang, G.G.,Kutateladze, T.G.
Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.
Nat Commun, 11:3339-3339, 2020

PubMed Abstract: Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.

PubMed: 32620764
DOI: 10.1038/s41467-020-17098-4

Experimental method

X-RAY DIFFRACTION (2.9 Å)