X-ray conformational analysis of the potent thyroliberin analogue l-pyroglutamyl-β-(2-thienyl)- l-alanyl- l-prolinamide

Abstract

The crystal and molecular structure of l-pyroglutamyl-β-(2-thienyl)- l-alanyl- l-prolinamide, < Glu-Thi-Pro-NH 2(Thi 2-TRH), C 17H 22N 4O 4S, has been determined from X-ray diffraction data. Thi 2-TRH is a highly active analogue of thyroliberin, a thyrotropin-releasing hormone (TRH), in which the imidazole ring of the central histidine moiety in the natural hormone has been replaced by a 2-thienyl group. Thi 2-TRH crystallizes from water in the monoclinic space group P2 1, a = 9.340(1) A ̊ , b = 21.961(3) A ̊ , c = 9.449(1) A ̊ and β = 109.58(1) °, with two molecules per asymmetric unit. These independent molecules, A and B, have the same general backbone conformation with the φ 2, ψ 2 and ψ 3 torsional angles close to −90 °, +120 ° and +150 °, respectively, but they show different magnitudes of rotational disorder in the thiophene ring as well as a certain disorder in the pyrrolidine ring. A and B are cross-linked by four interchain hydrogen bonds, forming a two-stranded antiparallel β-pleated sheet structure. The molecules in these dimer fragments are further hydrogen-bonded to successive translated molecules along the a and c axes, forming a pronounced two-dimensional predominantly hydrophobic layer structure. These layers, in which the atoms are almost equally arranged on both sides, are separated by ordinary van der Waals' distances. A close correlation between the molecular conformation in the solid state and the preferential conformation in solution is found. It is concluded that the crystalline structure of Thi 2-TRH possesses structural features which may be of relevance in the hormone-receptor interaction process.