title: [Ligand recognition mechanism of lipocalin-type prostaglandin D synthase].
abstract: Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a multi functional protein acting as a PGD(2) synthesizing enzyme, a transporter or scavenger of various lipophilic ligands, and an amyloid β chaperon in the brain. L-PGDS is a member of the lipocalin superfamily and has the ability to bind various lipophilic molecules such as prostanoid, retinoid, bile pigment, and amyloid β peptide. However, the molecular mechanism for a wide variety of ligand binding has not been well understood. In this study, we determined by NMR the structure of recombinant mouse L-PGDS and L-PGDS/PGH(2) analog complex. L-PGDS has the typical lipocalin fold, consisting of an eight-stranded β-barrel and a long α-helix. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins and the cavity contained two pockets. Kinetic studies and molecular docking studies based on the result of NMR titration experiments provide the direct evidence for two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS. Structural comparison of L-PGDS/U-46619 complex with apo-L-PGDS showed that the H2-helix, CD-loop, and EF-loop located at the upper end of the β-barrel change the conformation to cover the entry of the cavity upon U-46619 binding. These results indicated that the two binding sites in the large cavity and induced fit mechanism were responsible for the broad ligand specificity of L-PGDS.
authors: Faculty of Science and Technology, Kinki University, Osaka, Japan. sshimamoto@life.kindai.ac.jp
authors: Shigeru
authors: S
authors: Shimamoto
authors: Takuya
authors: T
authors: Yoshida
authors: Tadayasu
authors: T
authors: Ohkubo
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000502:physiology*; D008024:Ligands; D054834:Lipocalins / Q000737:chemistry* / Q000502:physiology*; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes; D019906:Nuclear Magnetic Resonance, Biomolecular; D044262:Prostaglandin H2; D011485:Protein Binding; D011487:Protein Conformation; D012890:Sleep / Q000235:genetics / Q000502:physiology; D014212:Tretinoin
chemical_list: D008024:Ligands; D054834:Lipocalins; D046912:Multiprotein Complexes; D044262:Prostaglandin H2; D014212:Tretinoin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase