title: Structural basis of compound recognition by adenosine deaminase.
abstract: Structural snapshots corresponding to various states enable elucidation of the molecular recognition mechanism of enzymes. Adenosine deaminase has two distinct conformations, an open form and a closed form, although it has so far been unclear what factors influence adaptation of the alternative conformations. Herein, we have determined the first nonligated structure as an initial state, which was the open form, and have thereby rationally deduced the molecular recognition mechanism. Inspection of the active site in the nonligated and ligated states indicated that occupancy at one of the water-binding positions in the nonligated state was highly significant in determining alternate conformations. When this position is empty, subsequent movement of Phe65 toward the space induces the closed form. On the other hand, while occupied, the overall conformation remains in the open form. This structural understanding should greatly assist structure-oriented drug design and enable control of the enzymatic activity.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Company, Ltd., 5-2-3, Tokodai, Tsukuba, Ibaraki 300-2698, Japan. kinotk@b.s.osakafu-u.ac.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Isao
authors.initials: I
authors.lastname: Nakanishi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terasaka
authors.forename: Masako
authors.initials: M
authors.lastname: Kuno
authors.forename: Nobuo
authors.initials: N
authors.lastname: Seki
authors.forename: Masaichi
authors.initials: M
authors.lastname: Warizaya
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Matsumura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Kazuhumi
authors.initials: K
authors.lastname: Takano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry* / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D014867:Water; D000243:Adenosine Deaminase