8j25 | pdb_00008j25

Crystal structure of PML B-box2 mutant

spinqualitylabelsall models 8j25, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8j25 is a 1 chain structure with sequence from Escherichia coli K-12 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: GLC, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PML_HUMAN Note=A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon. Function MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.PML_HUMAN Key component of PML nuclear bodies that regulate a large number of cellular processes by facilitating post-translational modification of target proteins, promoting protein-protein contacts, or by sequestering proteins. Functions as tumor suppressor. Required for normal, caspase-dependent apoptosis in response to DNA damage, FAS, TNF, or interferons. Plays a role in transcription regulation, DNA damage response, DNA repair and chromatin organization. Plays a role in processes regulated by retinoic acid, regulation of cell division, terminal differentiation of myeloid precursor cells and differentiation of neural progenitor cells. Required for normal immunity to microbial infections. Plays a role in antiviral response. In the cytoplasm, plays a role in TGFB1-dependent processes. Regulates p53/TP53 levels by inhibiting its ubiquitination and proteasomal degradation. Regulates activation of p53/TP53 via phosphorylation at 'Ser-20'. Sequesters MDM2 in the nucleolus after DNA damage, and thereby inhibits ubiquitination and degradation of p53/TP53. Regulates translation of HIF1A by sequestering MTOR, and thereby plays a role in neoangiogenesis and tumor vascularization. Regulates RB1 phosphorylation and activity. Required for normal development of the brain cortex during embryogenesis. Can sequester herpes virus and varicella virus proteins inside PML bodies, and thereby inhibit the formation of infectious viral particles. Regulates phosphorylation of ITPR3 and plays a role in the regulation of calcium homeostasis at the endoplasmic reticulum (By similarity). Regulates transcription activity of ELF4. Inhibits specifically the activity of the tetrameric form of PKM. Together with SATB1, involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Regulates PTEN compartmentalization through the inhibition of USP7-mediated deubiquitination. Publication Abstract from PubMed PML Nuclear Bodies (NBs) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% APL patients, 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 which could pave the way to novel cancer drugs. Structural basis of PML/RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function.,Bercier P, Wang QQ, Zang N, Zhang J, Yang C, Maimaitiyiming Y, Abou-Ghali M, Berthier C, Wu C, Niwa-Kawakita M, Dirami T, Geoffroy MC, Ferhi O, Quentin S, Benhenda S, Ogra Y, Gueroui Z, Zhou C, Naranmandura H, de The H, Lallemand-Breitenbach V Cancer Discov. 2023 Sep 1. doi: 10.1158/2159-8290.CD-23-0453. PMID:37655965 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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