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Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Lysine acetylation of human tumor suppressor p53 in response to cellular, stress signals is required for its function as a transcription factor that, regulates cell cycle arrest, senescence, or apoptosis. Here, we report, small molecules that block lysine 382-acetylated p53 association with the, bromodomain of the coactivator CBP, an interaction essential for, p53-induced transcription of the cell cycle inhibitor p21 in response to, DNA damage. These chemicals were discovered in target structure-guided, nuclear magnetic resonance spectroscopy screening of a focused chemical, library constructed based on the structural knowledge of CBP, bromodomain/p53-AcK382 binding. Structural characterization shows that, these chemicals inhibit CBP/p53 association by binding to the, acetyl-lysine binding site of the bromodomain. Cell-based functional, assays demonstrate that the lead chemicals can modulate p53 stability and, function in response to DNA damage.

Disease

Known diseases associated with this structure: Blue-cone monochromacy OMIM:[303900], Colorblindness, protan OMIM:[303900], Rubenstein-Taybi syndrome OMIM:[600140]

About this Structure

2D82 is a Single protein structure of sequence from Homo sapiens with TTR as ligand. Active as Histone acetyltransferase, with EC number 2.3.1.48 Full crystallographic information is available from OCA.

Reference

Target structure-based discovery of small molecules that block human p53 and CREB binding protein association., Sachchidanand, Resnick-Silverman L, Yan S, Mutjaba S, Liu WJ, Zeng L, Manfredi JJ, Zhou MM, Chem Biol. 2006 Jan;13(1):81-90. PMID:16426974

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