2WGX

HUMAN P53 CORE DOMAIN MUTANT M133L-V203A-Y236F-N239Y-T253I-N268D

2WGX の概要

• エントリーDOI: 10.2210/pdb2wgx/pdb
• 関連するPDBエントリー: 1A1U 1AIE 1C26 1DT7 1GZH 1H26 1HS5 1JSP 1KZY 1MA3 1OLG 1OLH 1PES 1PET 1SAE 1SAF 1SAH 1SAJ 1SAK 1SAL 1TSR 1TUP 1UOL 1XQH 1YCQ 1YCR 1YCS 2AC0 2ADY 2AHI 2ATA 2B3G 2BIM 2BIN 2BIO 2BIP 2BIQ 2F1X 2FEJ 2GS0 2H1L 2J0Z 2J10 2J11 2J1W 2J1X 2J1Y 2J1Z 2J20 2J21 2VUK 3SAK
• 分子名称: CELLULAR TUMOR ANTIGEN P53, ZINC ION (3 entities in total)
• 機能のキーワード: cell cycle, p53, p63, p73, cancer, nucleus, apoptosis, tumor suppressor, second-site suppressor mutation, dna-binding domain, transcription regulation, nuclear protein, protein stabilization, li-fraumeni syndrome, metal binding, zinc, superstable mutant, dna-binding protein, polymorphism
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49304.61

構造登録者

Joerger, A.C.,Khoo, K.H.,Fersht, A.R. (登録日: 2009-04-27, 公開日: 2009-05-12, 最終更新日: 2023-12-13)

主引用文献

Khoo, K.H.,Joerger, A.C.,Freund, S.M.V.,Fersht, A.R.
Stabilising the DNA-Binding Domain of P53 by Rational Design of its Hydrophobic Core.
Protein Eng.Des.Sel., 22:421-, 2009

PubMed Abstract: The core domain of the tumour suppressor p53 is of inherently low thermodynamic stability and also low kinetic stability, which leads to rapid irreversible denaturation. Some oncogenic mutations of p53 act by just making the core domain thermosensitive, and so it is the target of novel anti-cancer drugs that bind to and stabilise the protein. Increasing the stability of the unstable core domain has also been crucial for biophysical and structural studies, in which a stabilised quadruple mutant (QM) is currently used. We generated an even more stabilised hexamutant (HM) by making two additional substitutions, Y236F and T253I, to the QM. The residues are found in the more stable paralogs p63 and p73 and stabilise the wild-type p53 core domain. We solved the structure of the HM core domain by X-ray crystallography at 1.75 A resolution. It has minimal structural changes from QM that affect the packing of hydrophobic core residues of the beta-sandwich. The full-length HM was also fully functional in DNA binding. HM was more stable than QM at 37 degrees C. Anomalies in biophysics and spectroscopy in urea-mediated denaturation curves of HM implied the accumulation of a folding intermediate, which may be related to those detected in kinetic experiments. The two additional mutations over-stabilise an unfolding intermediate. These results should be taken into consideration in drug design strategies for increasing the stability of temperature-sensitive mutants of p53.

PubMed: 19515728
DOI: 10.1093/PROTEIN/GZP018

実験手法

X-RAY DIFFRACTION (1.75 Å)