8J2P

Crystal structure of PML B-box2

Summary for 8J2P

• Entry DOI: 10.2210/pdb8j2p/pdb
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Protein PML, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ZINC ION, ... (4 entities in total)
• Functional Keywords: pml, trim19, b-box2, ligase
• Biological source: Escherichia coli (strain K12); More
• Total number of polymer chains: 2
• Total formula weight: 94992.63

Authors

Zhou, C.,Zang, N.,Zhang, J. (deposition date: 2023-04-15, release date: 2023-09-20, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.09 Å)