| NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. | |
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MedLine Citation:
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PMID: 17715133 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), an endogenous somnogen and nociceptive modulator, in the brain. L-PGDS is a member of the lipocalin superfamily and binds lipophilic substances, such as retinoids and bile pigments, suggesting that L-PGDS is a dual functional protein acting as a PGD(2)-synthesizing enzyme and a transporter for lipophilic ligands. In this study we determined by NMR the three-dimensional structure of recombinant mouse L-PGDS with the catalytic residue Cys-65. The structure of L-PGDS exhibited the typical lipocalin fold, consisting of an eight-stranded, antiparallel beta-barrel and a long alpha-helix associated with the outer surface of the barrel. 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. Molecular docking studies, based on the result of NMR titration experiments with retinoic acid and PGH(2) analog, revealed that PGH(2) almost fully occupied the hydrophilic pocket 1, in which Cys-65 was located and all-trans-retinoic acid occupied the hydrophobic pocket 2, in which amino acid residues important for retinoid binding in other lipocalins were well conserved. Mutational and kinetic studies provide the direct evidence for the PGH(2) binding mode. These results indicated that the two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS were responsible for the broad ligand specificity of L-PGDS and the non-competitive inhibition of L-PGDS activity by retinoic acid. |
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Authors:
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Shigeru Shimamoto; Takuya Yoshida; Takashi Inui; Keigo Gohda; Yuji Kobayashi; Ko Fujimori; Toshiharu Tsurumura; Kosuke Aritake; Yoshihiro Urade; Tadayasu Ohkubo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-08-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 282 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-10-22 Completed Date: 2007-12-06 Revised Date: 2008-04-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 31373-9 Citation Subset: IM |
Affiliation:
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Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/2E4J |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Binding Sites Catalysis Hydrogen Bonding Hydrophobicity Intramolecular Oxidoreductases / chemistry*, genetics, metabolism* Kinetics Ligands Lipocalins / chemistry*, genetics, metabolism* Mice Models, Molecular Molecular Sequence Data Mutation Nitrogen Isotopes / metabolism Nuclear Magnetic Resonance, Biomolecular / methods* Protein Binding Protein Conformation Protein Folding Protein Structure, Secondary Protons Recombinant Proteins / chemistry, metabolism Titrimetry Tretinoin / chemistry* |
| Chemical | |
Reg. No./Substance:
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0/Ligands; 0/Lipocalins; 0/Nitrogen Isotopes; 0/Protons; 0/Recombinant Proteins; 302-79-4/Tretinoin; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.2/prostaglandin R2 D-isomerase |
| Comments/Corrections | |
Erratum In:
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J Biol Chem. 2008 Mar 28;283(13):8772 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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