title: LSD1/CoREST reversible opening-closing dynamics: discovery of a nanoscale clamp for chromatin and protein binding.
abstract: LSD1 associated with its corepressor protein CoREST is an exceptionally relevant target for epigenetic drugs. Hypotheses for the role of LSD1/CoREST as a multidocking site for chromatin and protein binding would require significant molecular flexibility, and LSD1/CoREST large-amplitude conformational dynamics is currently unknown. Here, molecular dynamics simulation reveals that the LSD1/CoREST complex in solution functions as a reversible nanoscale binding clamp. We show that the H3 histone tail binding pocket is a potential allosteric site for regulation of the rotation of SWIRM/SANT2 domains around the Tower domain. Thus, targeting this site and including receptor flexibility are crucial strategies for future drug discovery.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The Henry Eyring Center for Theoretical Chemistry, The University of Utah, Salt Lake City, Utah 84112, United States. r.baron@utah.edu
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
mesh_terms: D001665:Binding Sites; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; D006655:Histone Deacetylases