posted on 2021-02-19, 22:05authored byMrityunjay Singh, Mitul Srivastava, Sharad R. Wakode, Shailendra Asthana
Sirt1–3
are the most studied sirtuins, playing a key role
in caloric-dependent epigenetic modifications. Since they are localized
in distinct cellular compartments and act differently under various
pathological conditions, selective inhibition would be a promising
strategy to understand their biological function and to discover effective
therapeutics. Here, sirtuin’s inhibitor Ex527* is used as a
probe to speculate the possible root cause of selective inhibition
and differential structural dynamics of Sirt1–3. Comparative
energetics and mutational studies revealed the criticality of residues
I279 and I316 for the Sirt1 selectivity toward Ex527*. Furthermore,
essential dynamics and residue network analysis revealed that the
side-chain reorientation in residue F190 due to nonconserved residue
Y191 played a major role in the formation of an extended selectivity
pocket in Sirt2. These changes at the dynamical and residual level,
which impact the internal wiring significantly, might help in rationally
designing selective inhibitors against Sirt1–3.