4X3P

Sirt2 in complex with a myristoyl peptide

Summary for 4X3P

• Entry DOI: 10.2210/pdb4x3p/pdb
• Related: 4X3O
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, peptide PRO-LYS-LYS-THR-GLY, ZINC ION, ... (7 entities in total)
• Functional Keywords: sirt2, myristoyl peptide, hydrolase-peptide complex, hydrolase/peptide
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus. Isoform 1: Cytoplasm . Isoform 2: Cytoplasm . Isoform 5: Cytoplasm : Q8IXJ6
• Total number of polymer chains: 2
• Total formula weight: 35940.68

Authors

Wang, Y.,Zhang, W.,Hao, Q. (deposition date: 2014-12-01, release date: 2016-01-13, Last modification date: 2024-11-13)

Primary citation

Wang, Y.,Fung, Y.M.E.,Zhang, W.,He, B.,Chung, M.W.H.,Jin, J.,Hu, J.,Lin, H.,Hao, Q.
Deacylation Mechanism by SIRT2 Revealed in the 1'-SH-2'-O-Myristoyl Intermediate Structure.
Cell Chem Biol, 24:339-345, 2017

PubMed Abstract: Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II. In this intermediate, the covalent bond between the S and the myristoyl carbonyl carbon is broken, and we believe this intermediate III to be the decomposition product of II en route to form the end products. MALDI-TOF data further support the intermediate III formation. This is the first time such an intermediate has been captured by X-ray crystallography and provides more mechanistic insights into sirtuin-catalyzed reactions.

PubMed: 28286128
DOI: 10.1016/j.chembiol.2017.02.007

Experimental method

X-RAY DIFFRACTION (1.8 Å)