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Abstract

Histone deacetylase 6 (HDAC6) plays an essential role in the regulation of post-translational lysine acetylation. Myriad biological processes depend on the precise regulation of lysine acetylation-deacetylation cycles, and their dysregulation is linked to human pathologies such as cancer and neurodegeneration. Broad-specificity HDAC inhibitors are efficacious in treating disease, but the inhibitors currently approved for clinical use often cause deleterious side effects due to inhibition of multiple HDAC isozymes as well as other zinc enzymes. Cyclic peptides comprise novel platforms that, in principle, can be tailored for affinity and selectivity. A key advantage of cyclic peptide design is the ability to incorporate both canonical and noncanonical amino acids. As part of our program focusing on cyclic peptide HDAC inhibitors, we now report the 1.9-[A] resolution crystal structure of HDAC6 CD2 complexed with macrocyclic nonapeptide 1. The structure reveals zinc coordination by a noncanonical thiolate-containing amino acid, plus direct and water-mediated enzyme-inhibitor hydrogen bonds that contribute to nanomolar inhibitory potency. Structural comparisons with previously reported HDAC6 CD2 complexes with tetrapeptide and octapeptide macrocycles reveal similar networks of direct and water-mediated interactions. Given the surge of interest in cyclic peptide inhibitors, fueled in part by advances in computational design approaches, the crystal structure of the HDAC6 CD2-1 complex sets an important foundation for further development of macrocyclic peptide inhibitors.

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