title: Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor.
abstract: We comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding.
  
  
  
  All the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite.
  
  
  
  Our study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. nojimah@pharm.kitasato-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.|Present address: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kanou
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Terashi
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takeda-Shitaka
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Inoue
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Itoh
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Iguchi
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D014867:Water; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: Cocrystal structure; DPP-4 inhibitor; Dipeptidyl peptidase IV; In silico screening; Inhibitory activity; Water molecule