Document Detail


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.
MedLine Citation:
PMID:  17715133     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-08-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-22     Completed Date:  2007-12-06     Revised Date:  2008-04-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31373-9     Citation Subset:  IM    
Affiliation:
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Data Bank Information
Bank Name/Acc. No.:
PDB/2E4J
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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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