Abstract
Inhibiting the histone H3–ASF1 (anti-silencing function 1) protein–protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α-helix-mediated PPI, constraining the key histone H3 helix (residues 118–135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3 118–135 peptides bearing pentenylglycine residues at the i and i+4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy–entropy compensation occurs.
Original language | English |
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Pages (from-to) | 891-895 |
Number of pages | 5 |
Journal | ChemBioChem |
Volume | 20 |
Issue number | 7 |
DOIs | |
Publication status | Published - 1 Apr 2019 |
Bibliographical note
Funding Information:This work was supported by the Engineering and Physical Sciences Research Council [EP/N013573/1] and [EP/KO39292/1], the European Research Council [ERC-StG-240324], We thank the Well- come Trust [094232/Z/10/Z] and [097827/Z/11/A] for funding CD and HPLC facilities, respectively, the French ANR 2012 CHAPINHIB, the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INBS-05. M.E.P was supported by a programme foundation ARC (Agence de Recherche contre le Cancer), M.B. was supported by Canceropole (Paris, France), and a grant for young researchers from La Ligue contre le Cancer. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. MSCA-IF-2016-749012.
Funding Information:
This work was supported by the Engineering and Physical Sciences Research Council [EP/N013573/1] and [EP/KO39292/1], the European Research Council [ERC-StG-240324], We thank the Wellcome Trust [094232/Z/10/Z] and [097827/Z/11/A] for funding CD and HPLC facilities, respectively, the French ANR 2012 CHAPINHIB, the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INBS-05. M.E.P was supported by a programme foundation ARC (Agence de Recherche contre le Cancer), M.B. was supported by Canceropole (Paris, France), and a grant for young researchers from La Ligue contre le Cancer. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement no. MSCA-IF-2016-749012.
Publisher Copyright:
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Keywords
- chemical biology
- constrained peptides
- histone chaperones
- protein surface recognition
- protein–protein interactions
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Organic Chemistry