 |
PDBsum entry 4zzh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase activator
|
PDB id
|
|
|
|
4zzh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystallographic structure of a small molecule sirt1 activator-Enzyme complex.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
Nat Commun, 2015,
6,
7645.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
