Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction

Alexander V. Strizhak; Oleg Babii; Sergii Afonin; Iuliia Bakanovich; Teodors Pantelejevs; Wenshu Xu; Elaine Fowler; Rohan Eapen; Krishna Sharma; Maxim O. Platonov; Vasyl V. Hurmach; Laura Itzhaki; Marko Hyvönen; Anne S. Ulrich; David R. Spring; Igor V. Komarov

doi:10.1039/d0ob00831a

Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction

Alexander V. Strizhak, Oleg Babii, Sergii Afonin, Iuliia Bakanovich, Teodors Pantelejevs, Wenshu Xu, Elaine Fowler, Rohan Eapen, Krishna Sharma, Maxim O. Platonov, Vasyl V. Hurmach, Laura Itzhaki, Marko Hyvönen, Anne S. Ulrich^*, David R. Spring^*, Igor V. Komarov^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the "open"configuration, but up to eight times larger for the corresponding "closed"isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the "closed"isomers is mostly enthalpy-driven, whereas the "open"photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.

Original language	English
Pages (from-to)	5359-5369
Number of pages	11
Journal	Organic and Biomolecular Chemistry
Volume	18
Issue number	28
Early online date	11 May 2020
DOIs	https://doi.org/10.1039/d0ob00831a
Publication status	Published - 28 Jul 2020

Bibliographical note

Funding Information:
The authors acknowledge EU funding by the EU H2020-MSCA-RISE-2015 through the PELICO project (grant 690973). This work was also supported by the DFG-GRK 2039 (S.A., A.S.U.) and by the BMBF-VIP + (O.B., A.S.U.). TP’s doctoral studentship was supported by the Medical Research Council (UK). We thank Prof. Dr Burkhard Luy and Dr Claudia Muhle-Goll (KIT) for access to the ITC instrument. We also thank Diamond Light Source for access to macromolecular crystallography beam line i03 (proposal 18548) and for the data that contributed to these results. We are also grateful for access to and support by the X-ray Crystallographic and Biophysical Research Facility at the Department of Biochemistry, University of Cambridge.

Publisher Copyright:
© The Royal Society of Chemistry.

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Strizhak, A. V., Babii, O., Afonin, S., Bakanovich, I., Pantelejevs, T., Xu, W., Fowler, E., Eapen, R., Sharma, K., Platonov, M. O., Hurmach, V. V., Itzhaki, L., Hyvönen, M., Ulrich, A. S., Spring, D. R., & Komarov, I. V. (2020). Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction. Organic and Biomolecular Chemistry, 18(28), 5359-5369. https://doi.org/10.1039/d0ob00831a

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title = "Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction",

abstract = "Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the {"}open{"}configuration, but up to eight times larger for the corresponding {"}closed{"}isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the {"}closed{"}isomers is mostly enthalpy-driven, whereas the {"}open{"}photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.",

author = "Strizhak, {Alexander V.} and Oleg Babii and Sergii Afonin and Iuliia Bakanovich and Teodors Pantelejevs and Wenshu Xu and Elaine Fowler and Rohan Eapen and Krishna Sharma and Platonov, {Maxim O.} and Hurmach, {Vasyl V.} and Laura Itzhaki and Marko Hyv{\"o}nen and Ulrich, {Anne S.} and Spring, {David R.} and Komarov, {Igor V.}",

note = "Funding Information: The authors acknowledge EU funding by the EU H2020-MSCA-RISE-2015 through the PELICO project (grant 690973). This work was also supported by the DFG-GRK 2039 (S.A., A.S.U.) and by the BMBF-VIP + (O.B., A.S.U.). TP{\textquoteright}s doctoral studentship was supported by the Medical Research Council (UK). We thank Prof. Dr Burkhard Luy and Dr Claudia Muhle-Goll (KIT) for access to the ITC instrument. We also thank Diamond Light Source for access to macromolecular crystallography beam line i03 (proposal 18548) and for the data that contributed to these results. We are also grateful for access to and support by the X-ray Crystallographic and Biophysical Research Facility at the Department of Biochemistry, University of Cambridge. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry.",

year = "2020",

month = jul,

day = "28",

doi = "10.1039/d0ob00831a",

language = "English",

volume = "18",

pages = "5359--5369",

journal = "Organic and Biomolecular Chemistry",

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Strizhak, AV, Babii, O, Afonin, S, Bakanovich, I, Pantelejevs, T, Xu, W, Fowler, E, Eapen, R, Sharma, K, Platonov, MO, Hurmach, VV, Itzhaki, L, Hyvönen, M, Ulrich, AS, Spring, DR & Komarov, IV 2020, 'Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction', Organic and Biomolecular Chemistry, vol. 18, no. 28, pp. 5359-5369. https://doi.org/10.1039/d0ob00831a

TY - JOUR

T1 - Diarylethene moiety as an enthalpy-entropy switch

T2 - Photoisomerizable stapled peptides for modulating p53/MDM2 interaction

AU - Strizhak, Alexander V.

AU - Babii, Oleg

AU - Afonin, Sergii

AU - Bakanovich, Iuliia

AU - Pantelejevs, Teodors

AU - Xu, Wenshu

AU - Fowler, Elaine

AU - Eapen, Rohan

AU - Sharma, Krishna

AU - Platonov, Maxim O.

AU - Hurmach, Vasyl V.

AU - Itzhaki, Laura

AU - Hyvönen, Marko

AU - Ulrich, Anne S.

AU - Spring, David R.

AU - Komarov, Igor V.

N1 - Funding Information: The authors acknowledge EU funding by the EU H2020-MSCA-RISE-2015 through the PELICO project (grant 690973). This work was also supported by the DFG-GRK 2039 (S.A., A.S.U.) and by the BMBF-VIP + (O.B., A.S.U.). TP’s doctoral studentship was supported by the Medical Research Council (UK). We thank Prof. Dr Burkhard Luy and Dr Claudia Muhle-Goll (KIT) for access to the ITC instrument. We also thank Diamond Light Source for access to macromolecular crystallography beam line i03 (proposal 18548) and for the data that contributed to these results. We are also grateful for access to and support by the X-ray Crystallographic and Biophysical Research Facility at the Department of Biochemistry, University of Cambridge. Publisher Copyright: © The Royal Society of Chemistry.

PY - 2020/7/28

Y1 - 2020/7/28

N2 - Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the "open"configuration, but up to eight times larger for the corresponding "closed"isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the "closed"isomers is mostly enthalpy-driven, whereas the "open"photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.

AB - Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the "open"configuration, but up to eight times larger for the corresponding "closed"isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the "closed"isomers is mostly enthalpy-driven, whereas the "open"photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.

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U2 - 10.1039/d0ob00831a

DO - 10.1039/d0ob00831a

M3 - Article

C2 - 32390036

AN - SCOPUS:85088611038

SN - 1477-0520

VL - 18

SP - 5359

EP - 5369

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

IS - 28

ER -

Diarylethene moiety as an enthalpy-entropy switch: Photoisomerizable stapled peptides for modulating p53/MDM2 interaction

Abstract

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