User:Giang Thi Tuyet Nguyen/Sirt3BrResveratrol

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Structural highlights

Crystal Structure of hSirt3 in Complex with 4´-Bromo-Resveratrol and FdL-1 Peptide

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).

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