2VUK

Structure of the p53 core domain mutant Y220C bound to the stabilizing small-molecule drug PhiKan083

Summary for 2VUK

• Entry DOI: 10.2210/pdb2vuk/pdb
• Related: 1A1U 1AIE 1C26 1DT7 1GZH 1H26 1HS5 1JSP 1KZY 1MA3 1OLG 1OLH 1PES 1PET 1SAE 1SAF 1SAG 1SAH 1SAI 1SAJ 1SAK 1SAL 1TSR 1TUP 1UOL 1XQH 1YCQ 1YCR 1YCS 2AC0 2ADY 2AHI 2ATA 2B3G 2BIM 2BIN 2BIO 2BIP 2BIQ 2FEJ 2GS0 2H1L 2J0Z 2J10 2J11 2J1W 2J1X 2J1Y 2J1Z 2J20 2J21 3SAK
• Descriptor: CELLULAR TUMOR ANTIGEN P53, ZINC ION, 1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine, ... (4 entities in total)
• Functional Keywords: metal binding, phosphoprotein, ubl conjugation, activator, cell cycle, acetylation, methylation, zinc, cancer, nucleus, apoptosis, cytoplasm, tumor suppressor, virtual screening, second-site suppressor mutation, covalent protein-rna linkage, small-molecule drug, alternative splicing, p53 dna- binding domain, transcription regulation, nuclear protein, surface crevice, disease mutation, protein stabilization, host-virus interaction, li-fraumeni syndrome, endoplasmic reticulum, metal-binding, anti-oncogene, transcription, superstable mutant, dna-binding protein, dna binding, dna-binding, polymorphism, glycoprotein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 49430.77

Authors

Joerger, A.C.,Boeckler, F.M.,Fersht, A.R. (deposition date: 2008-05-26, release date: 2008-07-22, Last modification date: 2023-12-13)

Primary citation

Boeckler, F.M.,Joerger, A.C.,Jaggi, G.,Rutherford, T.J.,Veprintsev, D.B.,Fersht, A.R.
Targeted Rescue of a Destabilized Mutant of P53 by an in Silico Screened Drug.
Proc.Natl.Acad.Sci.USA, 105:10360-, 2008

PubMed Abstract: The tumor suppressor p53 is mutationally inactivated in approximately 50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in approximately 75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in silico analysis of the crystal structure using virtual screening and rational drug design. One of them, a carbazole derivative (PhiKan083), binds to the cavity with a dissociation constant of approximately 150 muM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein-PhiKan083 complex at 1.5-A resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimization. The Y220C mutant is an excellent "druggable" target for developing and testing novel anticancer drugs based on protein stabilization. We point out some general principles in relationships between binding constants, raising of melting temperatures, and increase of protein half-lives by stabilizing ligands.

PubMed: 18650397
DOI: 10.1073/PNAS.0805326105

Experimental method

X-RAY DIFFRACTION (1.5 Å)