6rcy
CRYSTAL STRUCTURE OF FK1 DOMAIN OF FKBP52 IN COMPLEX WITH A BIO-INSPIRED HYBRID FLUORESCENT LIGAND
Structural highlights
FunctionFKBP4_HUMAN Immunophilin protein with PPIase and co-chaperone activities (By similarity). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments (By similarity). The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 Forster 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 A resolution provided detailed information at the atomic scale, while also providing insight into native substrate binding. Bioinspired Hybrid Fluorescent Ligands for the FK1 Domain of FKBP52.,de la Sierra-Gallay IL, Belnou M, Chambraud B, Genet M, van Tilbeurgh H, Aumont-Nicaise M, Desmadril M, Baulieu EE, Jacquot Y, Byrne C J Med Chem. 2020 Sep 24;63(18):10330-10338. doi: 10.1021/acs.jmedchem.0c00825., Epub 2020 Sep 15. PMID:32866001[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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