Molecular modeling study for conformational changes of Sirtuin 2 due to substrate and inhibitor binding.
Sirtuin is a member of NAD(+)-dependent deacetylase family. The structural details of Sirtuin 2 (SIRT2) complex will be very useful to discover the drug which might have beneficial effects on various diseases like cancer, diabetes, etc. Unfortunately, SIRT2 complex structure is not available yet, hence molecular docking was carried out to dock the substrate (NAD(+) and acetylated lysine) and inhibitor (sirtinol) in the NAD(+) binding site. The suitable binding orientation of substrate and inhibitor in the SIRT2 active site was selected and subjected to 5 ns molecular dynamics simulations to adjust the binding orientation of inhibitor and substrate as well as to identify the conformational changes in the active site. The result provides an insight about 3D SIRT2 structural details as well as the importance of F96 in deacetylation function. In addition, our simulations revealed the displacement of F96 upon substrate and inhibitor binding, inducing an extended conformation of loop3 and changing its interactions with the rest of SIRT2. We believe that our study could be helpful to gain a structural insight of SIRT2 and to design the receptor-based inhibitors.
Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAAC), Gyeongsang National University (GNU), Gazha-dong, Jinju, Republic of Korea.
Sugunadevi
S
Sakkiah
Meganathan
M
Chandrasekaran
Yuno
Y
Lee
Songmi
S
Kim
Keun Woo
KW
Lee
D000595:Amino Acid Sequence; D001665:Binding Sites; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009243:NAD / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D056565:Sirtuin 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D056572:Histone Deacetylase Inhibitors; D009243:NAD; D056565:Sirtuin 2