STRUCTURE OF A PROTEIN IN A KINETIC TRAP

We have determined the structure of a metastable disulphide isomer of human insulin. Although not observed for proinsulin folding or insulin -chain recombination, the isomer retains ordered secondary structure a nd a compact hydrophobic cove. Comparison with native insulin reveals a global rearrangement in the orientation of A- and B-chains. One face of the protein's surface is nevertheless in common between native and non-native structures. This face contains receptor-binding determinan ts, rationalizing the partial biological activity of the isomer. Struc tures of native and non-native disulphide isomers also define alternat ive three-dimensional templates. Threading of insulin-like sequences p rovide an experimental realization of the inverse protein-folding prob lem.