8E7A

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

Summary for 8E7A

• Entry DOI: 10.2210/pdb8e7a/pdb
• Descriptor: Cellular tumor antigen p53, ZINC ION (3 entities in total)
• Functional Keywords: dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 24758.46

Authors

Lovell, S.,Liu, L.,Battaile, K.P.,Miller, S.,Karanicolas, J. (deposition date: 2022-08-23, release date: 2023-05-17, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.3 Å)