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Bioinspired Hybrid Fluorescent Ligands for the FK1 Domain of FKBP52.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-31 , DOI: 10.1021/acs.jmedchem.0c00825 Inès Li de la Sierra-Gallay 1 , Mathilde Belnou 2 , Béatrice Chambraud 3 , Melanie Genet 4 , Herman van Tilbeurgh 1 , Magali Aumont-Nicaise 1 , Michel Desmadril 1 , Etienne-Emile Baulieu 4 , Yves Jacquot 5 , Cillian Byrne 2, 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-31 , DOI: 10.1021/acs.jmedchem.0c00825 Inès Li de la Sierra-Gallay 1 , Mathilde Belnou 2 , Béatrice Chambraud 3 , Melanie Genet 4 , Herman van Tilbeurgh 1 , Magali Aumont-Nicaise 1 , Michel Desmadril 1 , Etienne-Emile Baulieu 4 , Yves Jacquot 5 , Cillian Byrne 2, 4
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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 Kd 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.
中文翻译：
FKBP52 FK1域的生物启发型杂交荧光配体。
FKBP52蛋白是类固醇激素受体共激活因子，可能与神经退行性疾病有关。描述了该蛋白质的FK1结构域的一系列小型水溶性生物启发型伪肽荧光配体。这种设计使得配体在该结构域的口袋中被吞噬时伴随着丹磺酰发色团的氢键结合，该丹磺酰发色团既是配体的组成部分，又是荧光报告分子。结合伴随着显着的波长偏移和配体荧光信号的增强。在结合的配体存在下激发FK1域天然色氨酸残基会导致Förster共振能量转移。进行了短序列内关键配体残基的变异，ķ d测定值。蛋白质配体复合物在2.30Å分辨率下的共结晶提供了原子级的详细信息，同时还提供了对天然底物结合的了解。
更新日期：2020-09-24
中文翻译：
FKBP52 FK1域的生物启发型杂交荧光配体。
FKBP52蛋白是类固醇激素受体共激活因子，可能与神经退行性疾病有关。描述了该蛋白质的FK1结构域的一系列小型水溶性生物启发型伪肽荧光配体。这种设计使得配体在该结构域的口袋中被吞噬时伴随着丹磺酰发色团的氢键结合，该丹磺酰发色团既是配体的组成部分，又是荧光报告分子。结合伴随着显着的波长偏移和配体荧光信号的增强。在结合的配体存在下激发FK1域天然色氨酸残基会导致Förster共振能量转移。进行了短序列内关键配体残基的变异，ķ d测定值。蛋白质配体复合物在2.30Å分辨率下的共结晶提供了原子级的详细信息，同时还提供了对天然底物结合的了解。
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