8J25

Crystal structure of PML B-box2 mutant

8J25 の概要

• エントリーDOI: 10.2210/pdb8j25/pdb
• 分子名称: Maltose/maltodextrin-binding periplasmic protein,Protein PML, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ZINC ION, ... (4 entities in total)
• 機能のキーワード: pml, trim19, b-box2, ligase
• 由来する生物種: Escherichia coli (strain K12); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47492.30

構造登録者

Zhou, C.,Zang, N.,Zhang, J. (登録日: 2023-04-14, 公開日: 2023-09-20, 最終更新日: 2023-12-20)

主引用文献

Bercier, P.,Wang, Q.Q.,Zang, N.,Zhang, J.,Yang, C.,Maimaitiyiming, Y.,Abou-Ghali, M.,Berthier, C.,Wu, C.,Niwa-Kawakita, M.,Dirami, T.,Geoffroy, M.C.,Ferhi, O.,Quentin, S.,Benhenda, S.,Ogra, Y.,Gueroui, Z.,Zhou, C.,Naranmandura, H.,de The, H.,Lallemand-Breitenbach, V.
Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.
Cancer Discov, 13:2548-2565, 2023

PubMed Abstract: PML nuclear bodies (NB) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs.

PubMed: 37655965
DOI: 10.1158/2159-8290.CD-23-0453

実験手法

X-RAY DIFFRACTION (2.6 Å)