Biophysical Probes Reveal a 鈥淐ompromise鈥?Nature of the Methyl-lysine Binding Pocket in L3MBTL1

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• 作者：Cen Gao ; J. Martin Herold ; Dmitri Kireev ; Tim Wigle ; Jacqueline L. Norris ; Stephen Frye
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：April 13, 2011
• 年：2011
• 卷：133
• 期：14
• 页码：5357-5362
• 全文大小：869K
• 年卷期：v.133,no.14(April 13, 2011)
• ISSN：1520-5126

文摘

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 鈥渂iophysical鈥?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 鈥渃ompromise鈥?that nonoptimally fits to both mono- and dimethyl-lysine marks.