The solution conformation of human big endothelin-1, a 38-residue peptide which serves as the putative precursor to the potent vasoconstrictor endothelin-1 has been examined by 1H NMR. NOEs were utilized as distance restraints in the distance geometry program DSPACE to generate initial structures. Further refinement of these structures was accomplished through molecular mechanics/molecular dynamics in an iterative process involving the incorporation of stereospecific assignments of prochiral centers and the use of back-calculation of NOESY spectra. A family of structures consisting of a type II beta-turn for residues 5-8 and an alpha-helix extending from residues 9-16 constitute a well-defined region, as reflected by the atomic root-mean-square (RMS) difference of 1.56 A about the mean coordinate positions of the backbone atoms (N, C, C alpha and O). This core region (residues 1-15) is very similar to the core residues of endothelin-1 (Donlan, M. et al. (1991) J. Cell. Biochemistry, S15G, 85). While the evidence from NOESY and coupling constant data suggests that the C-terminal region, residues 17-34, is not a mixture of randomly distributed chain conformations, it is also not consistent with a single chain conformation. Under the conditions studied, residues 17-38 in human big endothelin-1 in water at pH 3.0 between 20-30 degrees C appear to be represented by a series of conformers in dynamic equilibrium.