title: Photoreactive "nanorulers" detect a novel conformation of full length HDAC3-SMRT complex in solution.
abstract: Histone deacetylase 3 (HDAC3) is a promising epigenetic drug target for multiple therapeutic applications. Direct interaction between the Deacetylase Activating Domain of the silencing mediator for retinoid or thyroid-hormone receptors (SMRT-DAD) is required for activation of enzymatic activity of HDAC3. The structure of this complex and the nature of interactions with HDAC inhibitors in solution are unknown. Using novel photoreactive HDAC probes, "nanorulers", we determined the distance between the catalytic site of the full-length HDAC3 and SMRT-DAD in solution at physiologically relevant conditions and found it to be substantially different from that predicted by the X-ray model with a Δ379-428 aa truncated HDAC3. Further experiments indicated that in solution this distance might change in response to chemical stimuli, while the enzymatic activity remained unaffected. These observations were further validated by Saturation Transfer Difference (STD) NMR experiments. We propose that the observed changes in the distance are an important part of the histone code that remains to be explored. Mapping direct interactions and distances between macromolecules with such "nanorulers" as a function of cellular events facilitates better understanding of basic biology and ways for its manipulation in a cell- and tissue-specific manner.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Hazem
authors.initials: H
authors.lastname: Abdelkarim
authors.forename: Michael
authors.initials: M
authors.lastname: Brunsteiner
authors.forename: Raghupathi
authors.initials: R
authors.lastname: Neelarapu
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.forename: Antonett
authors.initials: A
authors.lastname: Madriaga
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Sylvie Y
authors.initials: SY
authors.lastname: Blond
authors.forename: Vadim
authors.initials: V
authors.lastname: Gaponenko
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
mesh_terms: D018360:Crystallography, X-Ray; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008027:Light; D008968:Molecular Conformation; D036103:Nanotechnology; D056985:Nuclear Receptor Co-Repressor 2 / Q000737:chemistry*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D056985:Nuclear Receptor Co-Repressor 2; D000099186:Histone Deacetylase 3