4l3o

Publication Abstract from PubMed

SIRT2 deacetylates specific acetyllysine residues in diverse proteins and is implicated in a variety of cellular processes. SIRT2 inhibition thus has potentials to treat human diseases such as cancers and neurodegenerative disorders. We have recently developed a series of epsilon-trifluoroacetyllysine-containing macrocyclic peptides, which inhibit the SIRT2 activity more potently than most other known inhibitors. Here, we report the crystal structure of human SIRT2 in complex with a macrocyclic peptide inhibitor, S2iL5, at 2.5 A resolution. The structure revealed that S2iL5 binds to the active site of SIRT2 through extensive interactions. A structural comparison of the SIRT2-S2iL5 complex with SIRT2 in the free form, and in complex with ADP-ribose, revealed that S2iL5 induces an open-to-closed domain movement and an unexpected helix-to-coil transition in a SIRT2-specific region. Our findings unveil the potential of macrocyclic peptides to bind target proteins by inducing dynamic structural changes.

Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change.,Yamagata K, Goto Y, Nishimasu H, Morimoto J, Ishitani R, Dohmae N, Takeda N, Nagai R, Komuro I, Suga H, Nureki O Structure. 2014 Feb 4;22(2):345-52. doi: 10.1016/j.str.2013.12.001. Epub 2014 Jan, 2. PMID:24389023^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.