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Novel Allosteric Me...
Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule
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- Grinkevich, Vera V. (author)
- Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden.
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- Vema, Aparna (author)
- Uppsala Univ, Dept Med Chem, Div Organ Pharmaceut Chem, Uppsala, Sweden.
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- Fawkner, Karin (author)
- Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden.
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- Issaeva, Natalia (author)
- Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA.
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- Andreotti, Virginia (author)
- IRCCS Osped Policlin San Martino, Genet Rare Canc, Genoa, Italy.
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- Dickinson, Eleanor R. (author)
- Univ Manchester, Manchester Inst Biotechnol, Sch Chem, Manchester, England.
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- Hedstrom, Elisabeth (author)
- Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden.
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- Spinnler, Clemens (author)
- Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden.
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- Inga, Alberto (author)
- Univ Trento, Dept CIBIO, Trento, Italy.
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- Larsson, Lars-Gunnar (author)
- Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden.
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- Karlen, Anders (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Wilhelm, Margareta (author)
- Karolinska Institutet
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- Barran, Perdita E. (author)
- Univ Manchester, Manchester Inst Biotechnol, Sch Chem, Manchester, England.
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- Okorokov, Andrei L. (author)
- UCL, Wolfson Inst Biomed Res, London, England.
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- Selivanova, Galina (author)
- Karolinska Institutet
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- Zawacka-Pankau, Joanna E. (author)
- Karolinska Institutet
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Karolinska Inst, Dept Microbiol, Tumor & Cell Biol, Stockholm, Sweden Uppsala Univ, Dept Med Chem, Div Organ Pharmaceut Chem, Uppsala, Sweden. (creator_code:org_t)
- 2022-06-01
- 2022
- English.
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In: Frontiers in Molecular Biosciences. - : Frontiers Media S.A.. - 2296-889X. ; 9
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Abstract
Subject headings
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- Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- p53
- N-terminus
- allosteric inhibition
- MDMX(4)
- MDM2
Publication and Content Type
- ref (subject category)
- art (subject category)
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Grinkevich, Vera ...
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Vema, Aparna
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Fawkner, Karin
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Issaeva, Natalia
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Andreotti, Virgi ...
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Dickinson, Elean ...
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Hedstrom, Elisab ...
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Spinnler, Clemen ...
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Inga, Alberto
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Larsson, Lars-Gu ...
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Karlen, Anders
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Wilhelm, Margare ...
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Barran, Perdita ...
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Okorokov, Andrei ...
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Selivanova, Gali ...
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Zawacka-Pankau, ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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MEDICAL AND HEAL ...
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and Basic Medicine
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Frontiers in Mol ...
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Uppsala University
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Karolinska Institutet