Abstract
In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.
Highlights
In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention
To uncover the structural basis of rescuing p53 mutants by methylene quinuclidinone (MQ) we investigated by X-ray crystallography high-resolution structures of the core domains of mutant and wild-type p53 bound to MQ in the absence and/or the presence of their DNA response elements
On the basis of the structural data in conjunction with previous biochemical and cell-based data on MQ binding to p53, we propose a mechanistic explanation for the functional rescue of oncogenic p53 as a tumor suppressor
Summary
In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. The human p53 tumor suppressor is a 393-residue protein that in response to cellular stress, acts as a transcription factor by binding as a tetramer to a wide range of DNA response elements, activating various events including DNA repair, cell-cycle arrest, senescence or apoptosis[1,2]. Mutations of arginine at positions 175, 248, 249, 273, 282, and of glycine at position 245 are referred as hotspots due to their high frequency in various types of cancer, comprising nearly 30% of the somatic mutations in the core domain[7,8,9] These mutations, located at or near the protein-DNA interface[10,11], lead to p53 inactivation by loss of direct p53-DNA interactions, and/or by causing conformational changes in the protein, resulting in lowering its stability[12,13,14,15]. The stability and folding states of the DNA-contact mutants are comparable to that of wild-type p53 whereas those of the structural mutants vary depending on the position and identity of the specific amino-acid replacement[15]
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