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Figure 4
The indole inhibitors CHIC35 and EX243 occupy the extended C-site (ECS) as well as the selectivity pocket with two molecules and induce a conformational change at the hinge region. (a) Chemical structures of CHIC35 and EX527 (racemic) and their IC50 values to inhibit deacetylation by Sirt1, Sirt2 and Sirt3 (taken from Napper et al., 2005BB47). The S-enantiomer of EX527 is termed EX243. (b) Surface representation of the catalytic core of Sirt2 in complex with ADPR. The corresponding subpockets of the catalytic core are labelled according to the literature. (c) An overlay of the improved structure of Sirt2–ADPR (grey), the Sirt2–ADPR–EX243 complex (light pink) and the Sirt2–ADPR–CHIC35 complex (salmon) reveals only minor differences in the overall structure; however, significant differences can be observed at the hinge region. (d) Close-up view of the hinge region of the structures shown in (c). The binding of the two indole molecules induces a 6 Å shift of one hinge loop. (e, f) Close-up view using the same orientation as shown in (c) of the active site of the Sirt2–ADPR–CHIC35 complex (e) and the Sirt2–ADPR–EX243 complex (f). ADPR is shown as turquoise (Sirt2–ADPR–CHIC35) or light yellow (Sirt2–ADPR–EX243) sticks. CHIC35 is shown as pale green sticks and EX243 as light blue sticks. To better differentiate between the two indole molecules, they are termed the ECS molecule and the hinge molecule, respectively. The σ-weighted 2FoFc electron-density map is contoured at 1.0σ. The cofactor-binding loop is not shown for the sake of clarity. σ-Weighted FoFc electron-density OMIT maps for ADPR and the indole inhibitors are shown in Supplementary Figs. S4 and S5.

ISSN: 2053-230X
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