4F56

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

Summary for 4F56

• Entry DOI: 10.2210/pdb4f56/pdb
• Related: 3RIG 3RIY 4f4u
• Descriptor: NAD-dependent lysine demalonylase and desuccinylase sirtuin-5, mitochondrial, peptide from Histone H3.1, ZINC ION, ... (5 entities in total)
• Functional Keywords: zn-binding domain, rossmann fold domain, nad-dependent demalonylase and desuccinylase, mitochondrial sirtuin, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion matrix. Isoform 1: Cytoplasm . Isoform 2: Mitochondrion : Q9NXA8; Nucleus: P68431
• Total number of polymer chains: 4
• Total formula weight: 63304.16

Authors

Zhou, Y.,Hao, Q. (deposition date: 2012-05-11, release date: 2012-06-20, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)