Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.
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 and a compact hydrophobic core. 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 determinants, rationalizing the partial biological activity of the isomer. Structures of native and non-native disulphide isomers also define alternative three-dimensional templates. Threading of insulin-like sequences provide an experimental realization of the inverse protein-folding problem.
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