3b99
Crystal structure of zebrafish prostacyclin synthase (cytochrome P450 8A1) in complex with substrate analog U51605Crystal structure of zebrafish prostacyclin synthase (cytochrome P450 8A1) in complex with substrate analog U51605
Structural highlights
FunctionPTGIS_DANRE Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2).[1] Catalyzes the biosynthesis and metabolism of eicosanoids. Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2), a potent mediator of vasodilation and inhibitor of platelet aggregation (PubMed:18032380). Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) (By similarity).[UniProtKB:Q16647][2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedProstacyclin synthase (PGIS) is a cytochrome P450 (P450) enzyme that catalyzes production of prostacyclin from prostaglandin H(2). 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 H(2), 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. Structures of prostacyclin synthase and its complexes with substrate analog and inhibitor reveal a ligand-specific heme conformation change.,Li YC, Chiang CW, Yeh HC, Hsu PY, Whitby FG, Wang LH, Chan NL J Biol Chem. 2008 Feb 1;283(5):2917-26. Epub 2007 Nov 21. PMID:18032380[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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