7X73

Structure of G9a in complex with RK-701

Summary for 7X73

• Entry DOI: 10.2210/pdb7x73/pdb
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, SINEFUNGIN, ... (7 entities in total)
• Functional Keywords: histone lysine methyltransferase, inhibitor, protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67697.32

Authors

Niwa, H.,Shirai, F.,Sato, S.,Nishigaya, Y.,Shirouzu, M.,Umehara, T. (deposition date: 2022-03-09, release date: 2022-12-21, Last modification date: 2023-11-29)

Primary citation

Takase, S.,Hiroyama, T.,Shirai, F.,Maemoto, Y.,Nakata, A.,Arata, M.,Matsuoka, S.,Sonoda, T.,Niwa, H.,Sato, S.,Umehara, T.,Shirouzu, M.,Nishigaya, Y.,Sumiya, T.,Hashimoto, N.,Namie, R.,Usui, M.,Ohishi, T.,Ohba, S.I.,Kawada, M.,Hayashi, Y.,Harada, H.,Yamaguchi, T.,Shinkai, Y.,Nakamura, Y.,Yoshida, M.,Ito, A.
A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression.
Nat Commun, 14:23-23, 2023

PubMed Abstract: Sickle cell disease (SCD) is a heritable disorder caused by β-globin gene mutations. Induction of fetal γ-globin is an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as therapeutic agents. However, the molecular mechanisms whereby these small molecules reactivate γ-globin remain unclear. Here we report the development of a highly selective and non-genotoxic G9a inhibitor, RK-701. RK-701 treatment induces fetal globin expression both in human erythroid cells and in mice. Using RK-701, we find that BGLT3 long non-coding RNA plays an essential role in γ-globin induction. RK-701 selectively upregulates BGLT3 by inhibiting the recruitment of two major γ-globin repressors in complex with G9a onto the BGLT3 gene locus through CHD4, a component of the NuRD complex. Remarkably, BGLT3 is indispensable for γ-globin induction by not only RK-701 but also hydroxyurea and other inducers. The universal role of BGLT3 in γ-globin induction suggests its importance in SCD treatment.

PubMed: 36635268
DOI: 10.1038/s41467-022-35404-0

Experimental method

X-RAY DIFFRACTION (1.49 Å)