4JSR

Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]

4JSR の概要

• エントリーDOI: 10.2210/pdb4jsr/pdb
• 関連するPDBエントリー: 4JT8 4JT9
• 分子名称: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, ZINC ION, N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide, ... (4 entities in total)
• 機能のキーワード: deacetylase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion matrix: Q9NTG7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32164.37

構造登録者

Dai, H. (登録日: 2013-03-22, 公開日: 2013-04-24, 最終更新日: 2024-02-28)

主引用文献

Disch, J.S.,Evindar, G.,Chiu, C.H.,Blum, C.A.,Dai, H.,Jin, L.,Schuman, E.,Lind, K.E.,Belyanskaya, S.L.,Deng, J.,Coppo, F.,Aquilani, L.,Graybill, T.L.,Cuozzo, J.W.,Lavu, S.,Mao, C.,Vlasuk, G.P.,Perni, R.B.
Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3.
J.Med.Chem., 56:3666-3679, 2013

PubMed Abstract: The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.

PubMed: 23570514
DOI: 10.1021/jm400204k

実験手法

X-RAY DIFFRACTION (1.7 Å)