6EQS

Human Sirt5 in complex with stalled peptidylimidate intermediate of inhibitory compound 29

6EQS の概要

• エントリーDOI: 10.2210/pdb6eqs/pdb
• 分子名称: NAD-dependent protein deacylase sirtuin-5, mitochondrial, ZINC ION, 3-[[(~{Z})-~{C}-[(2~{R},3~{R},4~{S},5~{R})-5-[[[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxymethyl]-3,4-bis(oxidanyl)oxolan-2-yl]sulfanyl-~{N}-[(5~{S})-6-[[(2~{S})-3-(1~{H}-indol-3-yl)-1-oxidanylidene-1-(propan-2-ylamino)propan-2-yl]amino]-6-oxidanylidene-5-(phenylmethoxycarbonylamino)hexyl]carbonimidoyl]amino]propanoic acid, ... (7 entities in total)
• 機能のキーワード: hydrolase, ptm, inhibitor, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion matrix. Isoform 1: Cytoplasm . Isoform 2: Mitochondrion : Q9NXA8
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 126442.51

構造登録者

Pannek, M.,Steegborn, C. (登録日: 2017-10-15, 公開日: 2017-11-01, 最終更新日: 2024-01-17)

主引用文献

Rajabi, N.,Auth, M.,Troelsen, K.R.,Pannek, M.,Bhatt, D.P.,Fontenas, M.,Hirschey, M.D.,Steegborn, C.,Madsen, A.S.,Olsen, C.A.
Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.
Angew. Chem. Int. Ed. Engl., 56:14836-14841, 2017

PubMed Abstract: The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more "drug-like" properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

PubMed: 29044784
DOI: 10.1002/anie.201709050

実験手法

X-RAY DIFFRACTION (1.32 Å)