title: Crystal structures of human dipeptidyl peptidase IV in its apo and diprotin B-complexed forms.
abstract: Dipeptidyl peptidase IV (DPPIV), which belongs to the prolyl oligopeptidase family of serine proteases, is known to have a variety of regulatory biological functions and has been shown to be implicated in type 2 diabetes. It is therefore important to develop selective human DPPIV (hDPPIV) inhibitors. In this study, we determined the crystal structure of apo hDPPIV at 1.9 A resolution. Our high-resolution crystal structure of apo hDPPIV revealed the presence of sodium ion and glycerol molecules at the active site. In order to elucidate the hDPPIV binding mode and substrate specificity, we determined the crystal structure of hDPPIV-diprotin B (Val-Pro-Leu) complex at 2.1 A resolution, and clarified the difference in binding mode between diprotin B and diprotin A (Ile-Pro-Ile) into the active site of hDPPIV. Comparison between our crystal structures and the reported apo hDPPIV structures revealed that positively charged functional groups and conserved water molecules contributed to the interaction of ligands with hDPPIV. These results are useful for the design of potent hDPPIV inhibitors.
authors.affiliation: Tanabe Seiyaku Co. Ltd, Osaka 532-8505, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hiramatsu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kyono
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Saeki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shima
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Koji
authors.initials: K
authors.lastname: Inaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Shimizu
mesh_terms: D001409:Bacillus cereus / Q000378:metabolism; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D015233:Models, Statistical; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D009842:Oligopeptides; D014867:Water; C041446:diprotin B; D018819:Dipeptidyl Peptidase 4; D010100:Oxygen