PUBLICATION
Probing Interaction between Prostacyclin Synthase and Prostaglandin H2 Analogues or Inhibitors via a Combination of Resonance Raman Spectroscopy and Molecular Dynamics Simulation Approaches
- Authors
- Chao, W.C., Lu, J.F., Wang, J.S., Yang, H.C., Chen, H.H., Lan, Y., Yu, Y.C., Chou, P.T., and Wang, L.H.
- ID
- ZDB-PUB-111024-12
- Date
- 2011
- Source
- Journal of the American Chemical Society 133(46): 18870-9 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System/chemistry*
- Cytochrome P-450 Enzyme System/metabolism
- Humans
- Intramolecular Oxidoreductases/antagonists & inhibitors
- Intramolecular Oxidoreductases/chemistry*
- Intramolecular Oxidoreductases/metabolism
- Ligands
- Models, Molecular
- Molecular Dynamics Simulation*
- Molecular Structure
- Prostaglandin H2/chemistry*
- Prostaglandin H2/metabolism
- Prostaglandins, Synthetic/chemistry*
- Prostaglandins, Synthetic/metabolism
- Spectrum Analysis, Raman*
- PubMed
- 21978190 Full text @ J. Am. Chem. Soc.
Citation
Chao, W.C., Lu, J.F., Wang, J.S., Yang, H.C., Chen, H.H., Lan, Y., Yu, Y.C., Chou, P.T., and Wang, L.H. (2011) Probing Interaction between Prostacyclin Synthase and Prostaglandin H2 Analogues or Inhibitors via a Combination of Resonance Raman Spectroscopy and Molecular Dynamics Simulation Approaches. Journal of the American Chemical Society. 133(46):18870-9.
Abstract
In an aim to probe the structure-function relationship of prostacyclin synthase (PGIS), resonance Raman (RR) spectroscopy and molecular dynamic (MD) simulation approaches have been exploited to characterize heme conformation and heme-protein matrix interactions for human PGIS (hPGIS) and zebrafish PGIS (zPGIS) in the presence and absence of ligands. The high-frequency RR (1300-1700cm-1) indicates that the heme group is in the ferric, six-coordinate, low-spin state for both resting and ligand-bound hPGIS/zPGIS. The low-frequency RR (300-500cm-1) and MD simulation reveal salient difference in propionate-protein matrix interactions between hPGIS and zPGIS, as evident by a predominant propionate bending vibration at 386 cm-1 in resting hPGIS, but two vibrations near 370 and 387 cm-1 in resting zPGIS. Upon binding of substrate analogue (U46619, U51605 or U44069), both hPGIS and zPGIS induce a distinctive perturbation of the propionate-protein matrix interactions, resulting in a similar Raman shifts to ~381 cm-1. On the contrary, the bending vibration remains unchanged upon binding of inhibitor/ligand (minoxidil, clotrimazole or miconazole), indicating that these inhibitors/ligands do not interfere with the propionate-protein matrix interactions. These results, together with subtle changes in vinyl bending modes, demonstrate drastically different RR shifts with heme conformational changes in both hPGIS and zPGIS upon different ligand binding, suggesting that PGIS exhibits a ligand-specific heme conformational change to accommodate the substrate binding. This substrate-induced modulation of heme conformation may confer high product fidelity upon PGIS catalysis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping