title: Biophysical probes reveal a "compromise" nature of the methyl-lysine binding pocket in L3MBTL1.
abstract: Histone lysine methylation (Kme) encodes essential information modulating many biological processes including gene expression and transcriptional regulation. However, the atomic-level recognition mechanisms of methylated histones by their respective adaptor proteins are still elusive. For instance, it is unclear how L3MBTL1, a methyl-lysine histone code reader, recognizes equally well both mono- and dimethyl marks but ignores unmodified and trimethylated lysine residues. We made use of molecular dynamics (MD) and free energy perturbation (FEP) techniques in order to investigate the energetics and dynamics of the methyl-lysine recognition. Isothermal titration calorimetry (ITC) was employed to experimentally validate the computational findings. Both computational and experimental methods were applied to a set of designed "biophysical" probes that mimic the shape of a single lysine residue and reproduce the binding affinities of cognate histone peptides. Our results suggest that, besides forming favorable interactions, the L3MBTL1 binding pocket energetically penalizes both methylation states and has most probably evolved as a "compromise" that nonoptimally fits to both mono- and dimethyl-lysine marks.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7363, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Gao
authors.forename: J Martin
authors.initials: JM
authors.lastname: Herold
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.forename: Tim
authors.initials: T
authors.lastname: Wigle
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Norris
authors.forename: Stephen
authors.initials: S
authors.lastname: Frye
mesh_terms: D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism*; D008745:Methylation; D056004:Molecular Dynamics Simulation; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D006657:Histones; D015335:Molecular Probes; D009687:Nuclear Proteins; D008239:Lysine