8E7A

Crystal structure of the p53 (Y107H) core domain orthorhombic P form

8E7A の概要

• エントリーDOI: 10.2210/pdb8e7a/pdb
• 分子名称: Cellular tumor antigen p53, ZINC ION (3 entities in total)
• 機能のキーワード: dna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24758.46

構造登録者

Lovell, S.,Liu, L.,Battaile, K.P.,Miller, S.,Karanicolas, J. (登録日: 2022-08-23, 公開日: 2023-05-17, 最終更新日: 2023-10-25)

主引用文献

Indeglia, A.,Leung, J.C.,Miller, S.A.,Leu, J.I.,Dougherty, J.F.,Clarke, N.L.,Kirven, N.A.,Shao, C.,Ke, L.,Lovell, S.,Barnoud, T.,Lu, D.Y.,Lin, C.,Kannan, T.,Battaile, K.P.,Yang, T.H.L.,Batista Oliva, I.,Claiborne, D.T.,Vogel, P.,Liu, L.,Liu, Q.,Nefedova, Y.,Cassel, J.,Auslander, N.,Kossenkov, A.V.,Karanicolas, J.,Murphy, M.E.
An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.
Cancer Discov, 13:1696-1719, 2023

PubMed Abstract: TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors.

PubMed: 37140445
DOI: 10.1158/2159-8290.CD-22-1315

実験手法

X-RAY DIFFRACTION (1.3 Å)