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MS-271 is a potent inhibitor of smooth muscle myosin light chain kinase (MLCK), obtained from Streptomyces sp. In the previous paper, we reported on the isolation, structural determination and biological properties of MS-271.(1) In this paper, we report on the three-dimensional structure of MS-271 determined by 1H NMR in deuterated dimethyl sulphoxide. MS-271 consists of 21 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Cysl, and two disulfide bonds, Cys1-Cys13 and Cys7-Cys19. The internal linkage between the side chain of Asp9 and the alpha-amino group of the N-terminal residue is the same as that of the endothelin B receptor selective antagonist, RES-701-1, that we previously reported. The structural calculations involved the combined use of distance geometry and simulated annealing calculations. The results indicated that MS-271 undergoes extraordinary folding, i.e. the "tail' (Phe10-dTrp21) passes through the "ring' region (Cys1-Asp9) ("lasso' structure). This folding of MS-271 turned out to be the same as the "lasso' structure of RES-701-1. The features of this "lasso' structure are discussed on the basis of comparison between the structures of MS-271 and RES-701-1.

The three-dimensional structure of the endothelin B receptor (ETB) selective antagonist RES-701-1 has been determined by 1H NMR in deuterated dimethyl sulphoxide. RES-701-1 consists of 16 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Gly1. The structural calculations were carried out with the combined use of distance geometry and simulated annealing. The result indicates that RES-701-1 adopts an extraordinary folding; the 'tail' (Trp10-Trp16) passes through the 'ring' region (Gly1-Asp9). Several critical NOEs directly support this extraordinary folding. The folding of RES-701-1 turned out to be the same as that Frèchet et al. calculated for RP 71955 which possesses the same internal linkage as RES-701-1. The obtained structure suggested that the region consisting of Thr6, Ala7, Tyr14 and Tyr15 and/or, the region consisting of Asn2, Tyr14 and Tyr15 are involved in a binding with ETB.