Structural basis for potent inhibition of SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change.

Abstract

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 ε-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 Å 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.

DOI: 10.1016/j.str.2013.12.001

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@article{Yamagata2014StructuralBF, title={Structural basis for potent inhibition of SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change.}, author={Kenichiro Yamagata and Yuki Goto and Hiroshi Nishimasu and Jumpei Morimoto and Ryuichiro Ishitani and Naoshi Dohmae and Norihiko Takeda and Ryozo Nagai and Issei Komuro and Hiroaki Suga and Osamu Nureki}, journal={Structure}, year={2014}, volume={22 2}, pages={345-52} }