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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). [3]
