Thromboxane molecules do not adopt the prostaglandin hairpin conformation

Abstract

The hairpin conformational hypothesis¹ has been proposed to rationalise much of the structure–activity and receptor-binding data which have accumulated for the prostaglandin (PG) hormones. The hairpin conformation, thought to be necessary for PG activity, requires that the α- and ω-chains of the molecule be extended and in parallel alignment, separated by a van der Waals contact distance for the full length of the chains, with the ends of the chains approximately 5.5 Å apart. The similarity between the structures of the thromboxanes (TXs) and the PGs suggests that the profile of activity of TXs, like that of PGs, centres on subtle conformational variation of the hairpin geometry. Thromboxane B₂ (TXB₂) is a stable hydrolysis product² of a highly reactive, short-lived intermediate³, thromboxane A₂ (TXA₂), which is formed from the prostaglandin endoperoxide (PGH₂) as indicated in Fig. 1. An examination of molecular models of TXA₂ and TXB₂ suggests that the struc tural differences between the ring moieties may have much less influence in altering the side-chain conformations of TXs than do substituents on the relatively more flexible cyclopentane ring of a PG molecule. We report here the first diffraction analysis of a thromboxane structure and note that the molecular conformation is not hairpin shaped.