User:Giang Thi Tuyet Nguyen/Sirt3BrResveratrol

This is a default text for your page Giang Thi Tuyet Nguyen/Sirt3BrResveratrol. Click above on edit this page to modify. Be careful with the < and > signs.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Function

Disease

Relevance

Structural highlights

Crystal Structure of hSirt3 in Complex with 4´-Bromo-Resveratrol and

In the resulting hSirt3/FdL-1/40-bromo-resveratrol complex structure, the compound was found in the active site. Interestingly, the inhibitor is arranged differently from the weaker inhibitor piceatannol in the previously solved hSirt3/FdL-1/piceatannol complex. A closer look at the compound binding site shows that the A-ring hydroxyl groups of 4´-bromo-resveratrol form hydrogen bonds with Asn229 and Asp231 of hSirt3. Furthermore, residues Ile230, Leu199, and Ile154 form a hydrophobic patch for A-ring binding, and Phe157, Leu195, and Phe180 a hydrophobic cleft for accommodating the B-ring. This cleft extends in a hydrophobic pocket (formed by Ile179, Leu173, and Tyr171) for binding the bromine atom, and Arg158 and Pro176 form a lid shielding this pocket from solvent.

Superposition of the hSirt3/FdL-1/4´-bromo-resveratrol complex with a structure of hSirt3 in complex with ACS2 peptide and the NAD+ analog carba-NAD+ (Szczepankiewicz et al., 2012) reveals that 4´-bromo-resveratrol occupies part of the NAD+ binding pocket, in particular the C-pocket. This arrangement prevents the insertion of the NAD+ nicotinamide moiety in the C-pocket necessary for catalysis, which indicates competitive inhibition with respect to this cosubstrate.

Crystal Structure of hSirt3 in Complex with ACS2 Substrate Peptide and 4´-Bromo-Resveratrol

Crystallizing hSirt3 in complex with ACS2 peptide, instead of FdL-1 peptide, in presence of 4´-bromo-resveratrol resulted in a different hSirt3/peptide/inhibitor arrangement. The compound molecule was found at the bottom of the Rossmann-fold domain,

interacting with Arg139, Met331, and Arg335, rather than in the catalytic pocket. In this exposed position, the compound interacts only through its A-ring with this shallow hSirt3 pocket, and the bromo-containing aromatic ring points toward the symmetry-related monomer in the crystal lattice. Superposition of the hSirt3/4´-bromo-resveratrol complexes with FdL-1 and ACS2 peptide, respectively, reveals that the inhibitor cannot bind at the catalytic pocket when the ACS2 peptide is bound, since it would clash with the C-terminal part of this substrate peptide. The obtained hSirt3/ACS2/ 4´-bromo-resveratrol complex can either show a different compound site and mechanism for 4´-bromo-resveratrol inhibition than the FdL-1 complex, or this second site is a crystallization artifact and the inhibitory site simply not occupied due to competition with the highly concentrated ACS2 peptide. In fact, 4´-bromo-resveratrol in the complex structure with hSirt3/ ACS2-peptide does not show many interactions with hSirt3, rendering it a less likely inhibition site. The hydrogen bonds of 4´-bromo-resveratrol with Arg139, Met331 (backbone), Arg335, and Arg384 of the symmetry-related monomer, and the very limited interaction interface with the hSirt3 monomer (see also Figure 3A).

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.