PUBLICATION
Structures of prostacyclin synthase and its complexes with substrate analog and inhibitor reveal a ligand-specific heme conformation change
- Authors
- Li, Y.C., Chiang, C.W., Yeh, H.C., Hsu, P.Y., Whitby, F.G., Wang, L.H., and Chan, N.L.
- ID
- ZDB-PUB-120117-26
- Date
- 2008
- Source
- The Journal of biological chemistry 382(5): 2917-2926 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Cloning, Molecular
- Crystallography, X-Ray
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System/chemistry*
- Cytochrome P-450 Enzyme System/genetics
- Cytochrome P-450 Enzyme System/metabolism
- Enzyme Inhibitors/pharmacology
- Epoprostenol/biosynthesis
- Heme/chemistry
- Intramolecular Oxidoreductases/antagonists & inhibitors
- Intramolecular Oxidoreductases/chemistry*
- Intramolecular Oxidoreductases/genetics
- Intramolecular Oxidoreductases/metabolism
- Ligands
- Minoxidil/pharmacology
- Models, Biological
- Models, Molecular
- Molecular Sequence Data
- Prostaglandins H/metabolism
- Protein Conformation
- Recombinant Proteins/antagonists & inhibitors
- Recombinant Proteins/chemistry
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Sequence Homology, Amino Acid
- Static Electricity
- Substrate Specificity
- Thermodynamics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 18032380 Full text @ J. Biol. Chem.
Citation
Li, Y.C., Chiang, C.W., Yeh, H.C., Hsu, P.Y., Whitby, F.G., Wang, L.H., and Chan, N.L. (2008) Structures of prostacyclin synthase and its complexes with substrate analog and inhibitor reveal a ligand-specific heme conformation change. The Journal of biological chemistry. 382(5):2917-2926.
Abstract
Prostacyclin synthase (PGIS) is a cytochrome P450 (P450) enzyme that catalyzes production of prostacyclin from prostaglandin
H2. PGIS is unusual in that it catalyzes an isomerization rather than a monooxygenation, which is typical of P450 enzymes. To
understand the structural basis for prostacyclin biosynthesis in greater detail, we have determined the crystal structures
of ligand-free, inhibitor (minoxidil)-bound and substrate analog U51605-bound PGIS. These structures demonstrate a stereo-specific
substrate binding and suggest features of the enzyme that facilitate isomerization. Unlike most microsomal P450s, where large
substrate-induced conformational changes take place at the distal side of the heme, conformational changes in PGIS are observed
at the proximal side and in the heme itself. The conserved and extensive heme propionate-protein interactions seen in all
other P450s, which are largely absent in the ligand-free PGIS, are recovered upon U51605 binding accompanied by water exclusion
from the active site. In contrast, when minoxidil binds, the propionate-protein interactions are not recovered and water molecules
are largely retained. These findings suggest that PGIS represents a divergent evolution of the P450 family, in which a heme
barrier has evolved to ensure strict binding specificity for prostaglandin H2, leading to a radical-mediated isomerization with high product fidelity. The U51605-bound structure also provides a view
of the substrate entrance and product exit channels.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping