PDBsum entry 4zzh

Hydrolase/hydrolase activator

PDB id: 4zzh

Contents

Protein chain

339 a.a.

Ligands

4TO

Metals

_ZN

PDB id:

4zzh

Name:

Hydrolase/hydrolase activator

Title:

Sirt1/activator complex

Structure:

NAD-dependent protein deacetylase sirtuin-1. Chain: a. Synonym: hsirt1,regulatory protein sir2 homolog 1,sir2-like protein 1,hsir2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sirt1, sir2l1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.10Å R-factor: 0.189 R-free: 0.238

Authors:

H.Dai

Key ref:

H.Dai et al. (2015). Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Nat Commun, 6, 7645. PubMed id: 26134520 DOI: 10.1038/ncomms8645

Date:

22-May-15 Release date: 15-Jul-15

Protein chain

Q96EB6  (SIR1_HUMAN) -  NAD-dependent protein deacetylase sirtuin-1 from Homo sapiens

Seq: 747 a.a.

Struc: 339 a.a.*

* PDB and UniProt seqs differ at 19 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.2.3.1.- - ?????
• Enzyme class 3: E.C.2.3.1.286 - protein acetyllysine N-acetyltransferase.
• Reaction: N₆-acetyl-L-lysyl-[protein] + NAD⁺ + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/ncomms8645

Nat Commun 6:7645 (2015)

PubMed id: 26134520

Crystallographic structure of a small molecule SIRT1 activator-enzyme complex.

H.Dai, A.W.Case, T.V.Riera, T.Considine, J.E.Lee, Y.Hamuro, H.Zhao, Y.Jiang, S.M.Sweitzer, B.Pietrak, B.Schwartz, C.A.Blum, J.S.Disch, R.Caldwell, B.Szczepankiewicz, C.Oalmann, P.Yee Ng, B.H.White, R.Casaubon, R.Narayan, K.Koppetsch, F.Bourbonais, B.Wu, J.Wang, D.Qian, F.Jiang, C.Mao, M.Wang, E.Hu, J.C.Wu, R.B.Perni, G.P.Vlasuk, J.L.Ellis.

ABSTRACT

SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.