4L3O

Crystal Structure of SIRT2 in complex with the macrocyclic peptide S2iL5

Summary for 4L3O

• Entry DOI: 10.2210/pdb4l3o/pdb
• Related PRD ID: PRD_001104
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, cyclic peptide S2iL5, ZINC ION, ... (6 entities in total)
• Functional Keywords: macrocyclic peptide, structural change, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm, cytoskeleton: Q8IXJ6
• Total number of polymer chains: 8
• Total formula weight: 146345.71

Authors

Yamagata, K.,Nishimasu, H.,Ishitani, R.,Nureki, O. (deposition date: 2013-06-06, release date: 2014-02-19, Last modification date: 2023-11-08)

Primary citation

Yamagata, K.,Goto, Y.,Nishimasu, H.,Morimoto, J.,Ishitani, R.,Dohmae, N.,Takeda, N.,Nagai, R.,Komuro, I.,Suga, H.,Nureki, O.
Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change
Structure, 22:345-352, 2013

PubMed 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.

PubMed: 24389023
DOI: 10.1016/j.str.2013.12.001

Experimental method

X-RAY DIFFRACTION (2.518 Å)