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The crystal structure of <scene name='69/699997/Hdac8_binding_substrate/3'>HDAC8-substrate complex</scene> shows that aspartate residue <scene name='69/699997/Hdac8_d101/2'>(D101)</scene> is important in the substrate binding <ref>Vannini, A. et al. Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports 8, 879–884 (2007).</ref>. The Asp 101 carboxylate moiety makes two consecutive hydrogen bonds with the backbone of the deacetylated peptide substrate. Mutation of Asp 101 to Ala inhibits HDAC8 activity. The Asp residue has been found to be strictly conserved among different HDAC isozymes.

[[Image:D101.png|400px|left|thumb| '''Fig. 2''' Mutation of Asp 101 to Ala inhibits HDAC8 activity.]]

Based on the crystallographic studies, a '''mechanism''' of the HDAC8 catalyzed reaction has been proposed.

[[Image:HDAC8_mechanism.png|400px|left|thumb| '''Fig. 3''' Catalytic mechanism of HDAC8.]]