MS-271, A novel inhibitor of calmodulin-activated myosin light chain kinase from Streptomyces sp.—II. Solution structure of MS-271: Characteristic features of the ‘lasso’ structure Original Research Article

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 β-carboxyl group of Asp9 and the α-amino group of Cys1, and two disulfide bonds, Cys1-Cys13 and Cys7-Cys19. The internal linkage between the side chain of Asp9 and the α-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.