Lill, Annika ; Schweipert, Markus ; Nehls, Thomas ; Wurster, Eva ; Lermyte, Frederik ; Meyer‐Almes, Franz‐Josef ; Schmitz, Katja (2024)
Design and synthesis of peptides as stabilizers of histone deacetylase 4.
In: Journal of Peptide Science, 2024, 30 (9)
doi: 10.26083/tuprints-00028278
Artikel, Zweitveröffentlichung, Verlagsversion
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Kurzbeschreibung (Abstract)
Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT‐motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit Ki values that are 9 to 56 times lower than that of the linear SMRT peptide. The peptide macrocycles stabilize the wildtype of the catalytic domain of HDAC4 (cHDAC4) considerably better than its thermally more stable ‘gain‐of‐function’ (GOF) variant, cHDAC4‐H976Y. Molecular docking and mutagenesis studies indicated that the cyclic peptides bind in a similar but not identical manner as the linear SMRT peptide to a discontinuous binding site. Ion mobility mass spectrometry showed no major changes in the protein fold upon peptide binding. Consistent with these results, preliminary hydrogen‐deuterium exchange mass spectrometry measurements indicated only minor conformational changes. Taken together, the cyclic SMRT peptides most likely stabilize the apo form of cHDAC4.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Lill, Annika ; Schweipert, Markus ; Nehls, Thomas ; Wurster, Eva ; Lermyte, Frederik ; Meyer‐Almes, Franz‐Josef ; Schmitz, Katja |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | Design and synthesis of peptides as stabilizers of histone deacetylase 4 |
| Sprache: | Englisch |
| Publikationsjahr: | 19 November 2024 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | September 2024 |
| Ort der Erstveröffentlichung: | New York |
| Verlag: | Wiley |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Journal of Peptide Science |
| Jahrgang/Volume einer Zeitschrift: | 30 |
| (Heft-)Nummer: | 9 |
| Kollation: | 9 Seiten |
| DOI: | 10.26083/tuprints-00028278 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/28278 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung DeepGreen |
| Kurzbeschreibung (Abstract): | Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT‐motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit Ki values that are 9 to 56 times lower than that of the linear SMRT peptide. The peptide macrocycles stabilize the wildtype of the catalytic domain of HDAC4 (cHDAC4) considerably better than its thermally more stable ‘gain‐of‐function’ (GOF) variant, cHDAC4‐H976Y. Molecular docking and mutagenesis studies indicated that the cyclic peptides bind in a similar but not identical manner as the linear SMRT peptide to a discontinuous binding site. Ion mobility mass spectrometry showed no major changes in the protein fold upon peptide binding. Consistent with these results, preliminary hydrogen‐deuterium exchange mass spectrometry measurements indicated only minor conformational changes. Taken together, the cyclic SMRT peptides most likely stabilize the apo form of cHDAC4. |
| Freie Schlagworte: | binding peptide, conformational stabilization, cyclization, histone deacetylase |
| ID-Nummer: | Artikel-ID: e3603 |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-282780 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie > Biologische Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie > Konformationssensitive Massenspektrometrie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 19 Nov 2024 12:20 |
| Letzte Änderung: | 20 Nov 2024 13:04 |
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| Suche nach Titel in: | TUfind oder in Google |
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- Design and synthesis of peptides as stabilizers of histone deacetylase 4. (deposited 19 Nov 2024 12:20) [Gegenwärtig angezeigt]
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