Recognition of Dimethylarginine Analogues by Tandem Tudor Domain Protein Spindlin1 |
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| Authors: | Miriam R B Porzberg Laust Moesgaard Catrine Johansson Udo Oppermann Jacob Kongsted Jasmin Mecinovi&#x; |
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| Institution: | 1.Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark; (M.R.B.P.); (L.M.); (J.K.);2.Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, NIHR Bio-Medical Research Centre, University of Oxford, Oxford OX3 7LD, UK; (C.J.); (U.O.) |
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| Abstract: | Epigenetic readout of the combinatorial posttranslational modification comprised of trimethyllysine and asymmetric dimethylarginine (H3K4me3R8me2a) takes place via biomolecular recognition of tandem Tudor-domain-containing protein Spindlin1. Through comparative thermodynamic data and molecular dynamics simulations, we sought to explore the binding scope of asymmetric dimethylarginine mimics by Spindlin1. Herein, we provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution. High-energy water molecules inside both aromatic cages of the ligand binding sites contribute to the reader–histone association upon displacement by histone peptide, with the K4me3 hydration site being lower in free energy due to a flip of Trp151. |
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| Keywords: | epigenetics histone arginine methylation molecular recognition reader protein |
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