Bioinspired Hybrid Fluorescent Ligands for the FK1 Domain of FKBP52.

Autor: de la Sierra-Gallay IL; Institut de Biologie Intégrative de la Cellule (I2BC), CNRS UMR9198, Université Paris-Saclay, Université Paris-Sud, 91405 Orsay, France., Belnou M; Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des biomolécules, LBM, 75005 Paris, France., Chambraud B; INSERM UMR 1195, Université Paris XI, 94270 Le Kremlin Bicêtre, France., Genet M; Institut Baulieu, INSERM UMR 1195, Neuroprotection et Neurorégénération, Université Paris-Saclay, 94270Le Kremlin Bicêtre, France., van Tilbeurgh H; Institut de Biologie Intégrative de la Cellule (I2BC), CNRS UMR9198, Université Paris-Saclay, Université Paris-Sud, 91405 Orsay, France., Aumont-Nicaise M; Institut de Biologie Intégrative de la Cellule (I2BC), CNRS UMR9198, Université Paris-Saclay, Université Paris-Sud, 91405 Orsay, France., Desmadril M; Institut de Biologie Intégrative de la Cellule (I2BC), CNRS UMR9198, Université Paris-Saclay, Université Paris-Sud, 91405 Orsay, France., Baulieu EE; Institut Baulieu, INSERM UMR 1195, Neuroprotection et Neurorégénération, Université Paris-Saclay, 94270Le Kremlin Bicêtre, France., Jacquot Y; Cibles Thérapeutiques et Conception de Médicaments (CiTCoM), CNRS UMR 8038, INSERM U1268, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, 75270 Paris Cedex 06, France., Byrne C; Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des biomolécules, LBM, 75005 Paris, France.; Institut Baulieu, INSERM UMR 1195, Neuroprotection et Neurorégénération, Université Paris-Saclay, 94270Le Kremlin Bicêtre, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 Sep 24; Vol. 63 (18), pp. 10330-10338. Date of Electronic Publication: 2020 Sep 15.
DOI: 10.1021/acs.jmedchem.0c00825
Abstrakt: The protein FKBP52 is a steroid hormone receptor coactivator likely involved in neurodegenerative disease. A series of small, water-soluble, bioinspired, pseudopeptidic fluorescent ligands for the FK1 domain of this protein are described. The design is such that engulfing of the ligand in the pocket of this domain is accompanied by hydrogen-bonding of the dansyl chromophore which functions as both an integral part of the ligand and a fluorescent reporter. Binding is concomitant with a significant wavelength shift and an enhancement of the ligand fluorescence signal. Excitation of FK1 domain native tryptophan residues in the presence of bound ligand results in Förster resonance energy transfer. Variation of key ligand residues within the short sequence was undertaken, and the interaction of the resulting library with the protein was measured by techniques including isothermal calorimetry analysis, fluorescence, and FRET quenching, and a range of K d values were determined. Cocrystallization of a protein ligand complex at 2.30 Å resolution provided detailed information at the atomic scale, while also providing insight into native substrate binding.
Databáze: MEDLINE
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