6RZ3

Crystal structure of a complex between the DNA-binding domain of p53 and the carboxyl-terminal conserved region of iASPP

Summary for 6RZ3

• Entry DOI: 10.2210/pdb6rz3/pdb
• Descriptor: Cellular tumor antigen p53, RelA-associated inhibitor, ZINC ION (3 entities in total)
• Functional Keywords: complex, p53, iaspp, antitumor protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 51857.63

Authors

Chen, S.,Ren, J.,Jones, E.Y.,Lu, X. (deposition date: 2019-06-12, release date: 2019-10-30, Last modification date: 2024-01-24)

Primary citation

Chen, S.,Wu, J.,Zhong, S.,Li, Y.,Zhang, P.,Ma, J.,Ren, J.,Tan, Y.,Wang, Y.,Au, K.F.,Siebold, C.,Bond, G.L.,Chen, Z.,Lu, M.,Jones, E.Y.,Lu, X.
iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition.
Proc.Natl.Acad.Sci.USA, 116:17470-17479, 2019

PubMed Abstract: The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

PubMed: 31395738
DOI: 10.1073/pnas.1909393116

Experimental method

X-RAY DIFFRACTION (4.23 Å)