title: Molecular modeling study on tunnel behavior in different histone deacetylase isoforms.
abstract: Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively. We have identified the equivalent tunnel forming amino acids in these three isoforms and found that they are very much conserved with subtle differences to be utilized in selective inhibitor development. One amino acid, methionine of HDAC8, among six tunnel forming residues is different in isoforms of other classes (glutamic acid (E) in HDAC10 and leucine (L) in HDAC 11) based on which mutations were introduced in HDAC11, the less studied HDAC isoform, to observe the effects of this change. The HDAC8-like (L268M) mutation in the tunnel forming residues has almost maintained the deep and narrow tunnel as present in HDAC8 whereas HDAC10-like (L268E) mutation has changed the tunnel wider and shallow as observed in HDAC10. These results explained the importance of the single change in the tunnel formation in different isoforms. The observations from this study can be utilized in the development of isoform-selective HDAC inhibitors.
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Gazwa-dong, Jinju, Republic of Korea.
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Shalini
authors.initials: S
authors.lastname: John
authors.forename: Yuno
authors.initials: Y
authors.lastname: Lee
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Arulalapperumal
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D006655:Histone Deacetylases