2f38
From Proteopedia
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Crystal structure of prostaglandin F synathase containing bimatoprost
Overview
Prostaglandin H(2) (PGH(2)) formed from arachidonic acid is an unstable, intermediate and is efficiently converted into more stable arachidonate, metabolites by the action of enzymes. Prostaglandin F synthase (PGFS) has, dual catalytic activities: formation of PGF(2)(alpha) from PGH(2) by the, PGH(2) 9,11-endoperoxide reductase activity and 9alpha,11beta-PGF(2), (PGF(2)(alphabeta)) from PGD(2) by the PGD(2) 11-ketoreductase activity in, the presence of NADPH. Bimatoprost (BMP), which is a highly effective, ocular hypotensive agent, is a PGF(2)(alpha) analogue that inhibits both, the PGD(2) 11-ketoreductase and PGH(2) 9,11-endoperoxide reductase, activities of PGFS. To examine the catalytic mechanism of PGH(2), 9,11-endoperoxide reductase, a crystal structure of PGFS[NADPH + BMP] has, been determined at 2.0 A resolution. BMP binds near the PGD(2) binding, site, but the alpha- and omega-chains of BMP are locate on the omega- and, alpha-chains of PGD(2), respectively. Consequently, the bound BMP and, PGD(2) direct their opposite faces of the cyclopentane moieties toward the, nicotinamide ring of the bound NADP. The alpha- and omega-chains of BMP, are involved in H-bonding with protein residues, while the cyclopentane, moiety is surrounded by water molecules and is not directly attached to, either the protein or the bound NADPH, indicating that the cyclopentane, moiety is movable in the active site. From the complex structure, two, model structures of PGFS containing PGF(2)(alpha) and PGH(2) were built., On the basis of the model structures and inhibition data, a putative, catalytic mechanism of PGH(2) 9,11-endoperoxide reductase of PGFS is, proposed. Formation of PGF(2)(alpha) from PGH(2) most likely involves a, direct hydride transfer from the bound NADPH to the endoperoxide of PGH(2), without the participation of specific amino acid residues.
About this Structure
2F38 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost., Komoto J, Yamada T, Watanabe K, Woodward DF, Takusagawa F, Biochemistry. 2006 Feb 21;45(7):1987-96. PMID:16475787
Page seeded by OCA on Fri Feb 15 17:24:43 2008
