5Y5N

Crystal structure of human Sirtuin 2 in complex with a selective inhibitor

Summary for 5Y5N

• Entry DOI: 10.2210/pdb5y5n/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, 2-[[3-(2-phenylethoxy)phenyl]amino]benzamide, ... (4 entities in total)
• Functional Keywords: pseudopeptides, anticancer activity, neurite outgrowth, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38234.19

Authors

Mellini, P.,Itoh, Y.,Tsumoto, H.,Li, Y.,Suzuki, M.,Tokuda, N.,Kakizawa, T.,Miura, Y.,Takeuchi, J.,Lahtela-Kakkonen, M.,Suzuki, T. (deposition date: 2017-08-09, release date: 2017-09-06, Last modification date: 2023-11-22)

Primary citation

Mellini, P.,Itoh, Y.,Tsumoto, H.,Li, Y.,Suzuki, M.,Tokuda, N.,Kakizawa, T.,Miura, Y.,Takeuchi, J.,Lahtela-Kakkonen, M.,Suzuki, T.
Potent mechanism-based sirtuin-2-selective inhibition by anin situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD+-binding site.
Chem Sci, 8:6400-6408, 2017

PubMed Abstract: Sirtuin 2 (SIRT2), a member of the NAD-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (), we identified in this study the potent mechanism-based inactivator KPM-2 (), which is selective toward SIRT2. Compound engages in a nucleophilic attack toward NAD at the active site of SIRT2, which affords a stable -ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the "selectivity pocket" and the NAD-binding site. Moreover, exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.

PubMed: 28989670
DOI: 10.1039/c7sc02738a

Experimental method

X-RAY DIFFRACTION (2.3 Å)