By a News Reporter-Staff News Editor at Life Science Weekly -- Investigators discuss new findings in Proteins. According to news reporting originating from Salt Lake City, Utah, by NewsRx correspondents, research stated, "Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date."
Our news editors obtained a quote from the research from the University of Utah, "Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain."
According to the news editors, the research concluded: "This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners."
For more information on this research see: Expanding the druggable space of the LSD1/CoREST epigenetic target: new potential binding regions for drug-like molecules, peptides, protein partners, and chromatin. Plos Computational Biology, 2013;9(7):e1003158. (Public Library of Science - www.plos.org; Plos Computational Biology - www.ploscompbiol.org)
The news editors report that additional information may be obtained by contacting J.C. Robertson, Dept. of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, United States. Additional authors for this research include N.C. Hurley, M. Tortorici, G. Ciossani, M.T. Borrello, N.A. Vellore, A. Ganesan, A. Mattevi and R. Baron (see also Proteins).
Keywords for this news article include: Utah, Genetics, Peptides, Chromatin, Amino Acids, United States, Salt Lake City, Nucleoproteins, North and Central America.
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