title: 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.
authors.affiliation: Department of Cardiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamagata
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 2-11-16, Yayoi, Bunkyo, Tokyo 113-0032, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimasu
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Morimoto
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 2-11-16, Yayoi, Bunkyo, Tokyo 113-0032, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Biomolecular Characterization Team and CREST/JST, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.affiliation: Department of Cardiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Cardiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan. Electronic address: hsuga@chem.s.u-tokyo.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 2-11-16, Yayoi, Bunkyo, Tokyo 113-0032, Japan. Electronic address: nureki@biochem.s.u-tokyo.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D006801:Humans; D007700:Kinetics; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020349:Surface Plasmon Resonance
chemical_list: D047028:Macrocyclic Compounds; D010455:Peptides; D010456:Peptides, Cyclic; D000246:Adenosine Diphosphate Ribose; C474199:SIRT2 protein, human; D056565:Sirtuin 2