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Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3
and Sirt2 suitable for soaking
#MMPMID26625292
Rumpf T
; Gerhardt S
; Einsle O
; Jung M
Acta Crystallogr F Struct Biol Commun
2015[Dec]; 71
(Pt 12
): 1498-510
PMID26625292
show ga
Sirtuins constitute a family of NAD(+)-dependent enzymes that catalyse the
cleavage of various acyl groups from the ?-amino group of lysines. They regulate
a series of cellular processes and their misregulation has been implicated in
various diseases, making sirtuins attractive drug targets. To date, only a few
sirtuin modulators have been reported that are suitable for cellular research and
their development has been hampered by a lack of structural information. In this
work, microseed matrix seeding (MMS) was used to obtain crystals of human Sirt3
in its apo form and of human Sirt2 in complex with ADP ribose (ADPR). Crystal
formation using MMS was predictable, less error-prone and yielded a higher number
of crystals per drop than using conventional crystallization screening methods.
The crystals were used to solve the crystal structures of apo Sirt3 and of Sirt2
in complex with ADPR at an improved resolution, as well as the crystal structures
of Sirt2 in complex with ADPR and the indoles EX527 and CHIC35. These
Sirt2-ADPR-indole complexes unexpectedly contain two indole molecules and provide
novel insights into selective Sirt2 inhibition. The MMS approach for Sirt2 and
Sirt3 may be used as the basis for structure-based optimization of Sirt2/3
inhibitors in the future.
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