Journal Article

Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)

Abrahmsén, Lars, Rozenberg, Haim, Golovenko, Dmitrij, Shakked, Zippora, Diskin-Posner, Yael, Degtjarik, Oksana

2021

Overview

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-1 MET ) 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. The tumor suppressor p53 is mutated in more than half of human cancers and the compound methylene quinuclidinone (MQ) was shown to reactivate p53 mutants by binding covalently to cysteine residues. Here, the authors present crystal structures of wild-type and cancer related p53 mutant core domains bound to MQ alone and in complex with their DNA response elements and observe that MQ is bound to several cysteine residues located at the surface of the core domain.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/45/535 / 631/535/1266 / 692/4028/67 / 82/16 / 82/80 / 82/83 / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Aza Compounds - chemistry / Aza Compounds - pharmacology / Aza Compounds - therapeutic use / Binding / Bioactive compounds / Biological activity / Bridged Bicyclo Compounds, Heterocyclic - chemistry / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Bridged Bicyclo Compounds, Heterocyclic - therapeutic use / Cancer / Crystal structure / Crystallography, X-Ray / Cysteine / Deoxyribonucleic acid / DNA / Domains / Gene expression / Genotoxicity / Humanities and Social Sciences / Humans / Loss of Function Mutation - drug effects / Methylene / multidisciplinary / Mutants / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / p53 Protein / Protein Domains - drug effects / Quinuclidines - chemistry / Quinuclidines - pharmacology / Quinuclidines - therapeutic use / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Recombinant Proteins - ultrastructure / Regulatory sequences / Residues / Science / Science (multidisciplinary) / Tumor suppressor genes / Tumor Suppressor Protein p53 - agonists / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - isolation & purification / Tumor Suppressor Protein p53 - ultrastructure / Tumors