4F56

The bicyclic intermediate structure provides insights into the desuccinylation mechanism of SIRT5

4F56 の概要

• エントリーDOI: 10.2210/pdb4f56/pdb
• 関連するPDBエントリー: 3RIG 3RIY 4f4u
• 分子名称: NAD-dependent lysine demalonylase and desuccinylase sirtuin-5, mitochondrial, peptide from Histone H3.1, ZINC ION, ... (5 entities in total)
• 機能のキーワード: zn-binding domain, rossmann fold domain, nad-dependent demalonylase and desuccinylase, mitochondrial sirtuin, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Mitochondrion matrix. Isoform 1: Cytoplasm . Isoform 2: Mitochondrion : Q9NXA8; Nucleus: P68431
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 63304.16

構造登録者

Zhou, Y.,Hao, Q. (登録日: 2012-05-11, 公開日: 2012-06-20, 最終更新日: 2024-10-16)

主引用文献

Zhou, Y.,Zhang, H.,He, B.,Du, J.,Lin, H.,Cerione, R.A.,Hao, Q.
The Bicyclic Intermediate Structure Provides Insights into the Desuccinylation Mechanism of Human Sirtuin 5 (SIRT5)
J.Biol.Chem., 287:28307-28314, 2012

PubMed Abstract: Sirtuins are pivotal regulators in various cellular processes, including transcription, DNA repair, genome stability, and energy metabolism. Their functions have been generally attributed to NAD-dependent deacetylase activity. However, human SIRT5 (sirtuin 5), which has been reported to exhibit little deacetylase activity, was recently identified as an NAD-dependent demalonylase and desuccinylase. Biochemical studies suggested that the mechanism of SIRT5-catalyzed demalonylation and desuccinylation is similar to that of deacetylation catalyzed by other sirtuins. Previously, we solved the crystal structure of a SIRT5-succinyl-lysine peptide-NAD complex. Here, we present two more structures: a binary complex of SIRT5 with an H3K9 succinyl peptide and a binary complex of SIRT5 with a bicyclic intermediate obtained by incubating SIRT5-H3K9 thiosuccinyl peptide co-crystals with NAD. To our knowledge, this represents the first bicyclic intermediate for a sirtuin-catalyzed deacylation reaction that has been captured in a crystal structure, thus providing unique insights into the reaction mechanism. The structural information should benefit the design of specific inhibitors for SIRT5 and help in exploring the therapeutic potential of targeting sirtuins for treating human diseases.

PubMed: 22767592
DOI: 10.1074/jbc.M112.384511

実験手法

X-RAY DIFFRACTION (1.7 Å)