4L3O: Crystal Structure Of Sirt2 In Complex With The Macrocyclic Peptide S2il5

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.
PDB ID: 4L3ODownload
MMDB ID: 117645
PDB Deposition Date: 2013/6/6
Updated in MMDB: 2014/02
Experimental Method:
x-ray diffraction
Resolution: 2.52  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4L3O: dimeric; determined by author and by software (PISA)
Molecular Components in 4L3O
Label Count Molecule
Proteins (2 molecules)
Nad-dependent Protein Deacetylase Sirtuin-2(Gene symbol: SIRT2)
Molecule annotation
Cyclic Peptide S2il5
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB