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On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis |
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| Authors: | Haider Shozeb Joseph Caleb G Neidle Stephen Fierke Carol A Fuchter Matthew J |
| Affiliation: | a Centre for Cancer Research and Cell Biology, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK b Department of Medicinal Chemistry, University of Michigan, 930 North University, Ann Arbor, Michigan 48109, USA c Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, London, UK d Department of Chemistry, Department of Biological Chemistry, University of Michigan, 930 North University, Ann Arbor, Michigan 48109, USA e Department of Chemistry, Imperial College London, London SW7 2AZ, UK |
| Abstract: | Biochemical studies reveal that a conserved arginine residue (R37) at the centre of the 14 Å internal cavity of histone deacetylase (HDAC) 8 is important for catalysis and acetate affinity. Computational studies indicate that R37 forms multiple hydrogen bonding interactions with the backbone carbonyl oxygen atoms of two conserved glycine residues, G303 and G305, resulting in a ‘closed’ form of the channel. One possible rationale for these data is that water or product (acetate) transit through the catalytically crucial internal channel of HDAC8 is regulated by a gating interaction between G139 and G303 tethered in position by the conserved R37. |
| Keywords: | HDAC Epigenetic Chromatin Histones Acetylation |
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