4ZZI
SIRT1/Activator/Inhibitor Complex
Summary for 4ZZI
| Entry DOI | 10.2210/pdb4zzi/pdb |
| Descriptor | NAD-dependent protein deacetylase sirtuin-1, (3S)-1,3-dimethyl-N-[3-(1,3-oxazol-5-yl)phenyl]-6-[3-(trifluoromethyl)phenyl]-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide, 4-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide, ... (5 entities in total) |
| Functional Keywords | sirtuin, activator, deacylase, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Nucleus, PML body. SirtT1 75 kDa fragment: Cytoplasm: Q96EB6 |
| Total number of polymer chains | 1 |
| Total formula weight | 41067.64 |
| Authors | |
| Primary citation | Dai, H.,Case, A.W.,Riera, T.V.,Considine, T.,Lee, J.E.,Hamuro, Y.,Zhao, H.,Jiang, Y.,Sweitzer, S.M.,Pietrak, B.,Schwartz, B.,Blum, C.A.,Disch, J.S.,Caldwell, R.,Szczepankiewicz, B.,Oalmann, C.,Yee Ng, P.,White, B.H.,Casaubon, R.,Narayan, R.,Koppetsch, K.,Bourbonais, F.,Wu, B.,Wang, J.,Qian, D.,Jiang, F.,Mao, C.,Wang, M.,Hu, E.,Wu, J.C.,Perni, R.B.,Vlasuk, G.P.,Ellis, J.L. Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Nat Commun, 6:7645-7645, 2015 Cited by PubMed 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. PubMed: 26134520DOI: 10.1038/ncomms8645 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7346 Å) |
Structure validation
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