4RMH

Human Sirt2 in complex with SirReal2 and Ac-Lys-H3 peptide

Summary for 4RMH

• Entry DOI: 10.2210/pdb4rmh/pdb
• Related: 4RMG 4RMI 4RMJ
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, Ac-Lys-H3 peptide, ZINC ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus. Isoform 1: Cytoplasm . Isoform 2: Cytoplasm . Isoform 5: Cytoplasm : Q8IXJ6
• Total number of polymer chains: 2
• Total formula weight: 35631.50

Authors

Rumpf, T.,Schiedel, M.,Karaman, B.,Roessler, C.,North, B.J.,Lehotzky, A.,Olah, J.,Ladwein, K.I.,Schmidtkunz, K.,Gajer, M.,Pannek, M.,Steegborn, C.,Sinclair, D.A.,Gerhardt, S.,Ovadi, J.,Schutkowski, M.,Sippl, W.,Einsle, O.,Jung, M. (deposition date: 2014-10-21, release date: 2015-02-25, Last modification date: 2024-11-20)

Primary citation

Rumpf, T.,Schiedel, M.,Karaman, B.,Roessler, C.,North, B.J.,Lehotzky, A.,Olah, J.,Ladwein, K.I.,Schmidtkunz, K.,Gajer, M.,Pannek, M.,Steegborn, C.,Sinclair, D.A.,Gerhardt, S.,Ovadi, J.,Schutkowski, M.,Sippl, W.,Einsle, O.,Jung, M.
Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.
Nat Commun, 6:6263-6263, 2015

PubMed Abstract: Sirtuins are a highly conserved class of NAD(+)-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology.

PubMed: 25672491
DOI: 10.1038/ncomms7263

Experimental method

X-RAY DIFFRACTION (1.42 Å)