Figure 1.

A total of 17 missense mutations in HDAC8 have been identified to date in children diagnosed with Cornelia de Lange Syndrome. Mutations (red) are mapped onto the structure of the Y306F HDAC8–substrate complex (PDB accession code 2V5W; note that the Y240N mutation is accompanied by the deletion of K239). The bound substrate, Ac-Arg-His-Lys(Ac)-Lys(Ac)-aminomethylcoumarin, is a gray stick-figure, and the active site Zn²⁺ ion is a dark blue sphere. Monovalent cations required for structural stabilization and regulation of catalytic activity are shown as orange and green spheres. Purple and cyan segments indicate the flexible L1 and L2 loops, respectively, which can undergo conformational changes to accommodate substrate and inhibitor binding.