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Engineering human glycoprotein hormone superactive analogues

Nature Biotechnology volume 14, pages 1257–1263 (1996)Cite this article

Abstract

We report the generation of superactive analogues of human glycoprotein hormones, with potential applications in thyroid and reproductive disorders. Current biological and structural data were used to rationalize mutagenesis. The 11–20 region in the α-subunit with a cluster of lysine residues forms a previously unrecognized domain critical for receptor binding and signal transduction, as well as an important motif in the evolution of glycoprotein hormone activities. The gradual elimination of basic residues in the α-subunit coincided with the evolutionary divergence of the hominids from the Old World monkeys. By selective reconstitution of certain critical residues present in homologous nonhuman hormones we have developed human thyroid stimulating hormone and chorionic gonadotropin analogues with substantial increases in receptor binding affinity and bioactivity, thus providing a paradigm for the design of novel therapeutic protein analogues.

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Author notes

  1. Mariusz W. Szkudlinski: e-mail: szkudlin@umbi.umd.edu

Authors and Affiliations

  1. Laboratory of Molecular Endocrinology, Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, 725 West Lombard St., Baltimore, MD, 21201

    Mariusz W. Szkudlinski, Mathis Grossmann & Bruce D. Weintraub

  2. Molecular and Cellular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892

    Nenita G. Teh & Joseph E. Tropea

Authors
  1. Mariusz W. Szkudlinski
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  5. Bruce D. Weintraub
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Szkudlinski, M., Teh, N., Grossmann, M. et al. Engineering human glycoprotein hormone superactive analogues. Nat Biotechnol 14, 1257–1263 (1996). https://doi.org/10.1038/nbt1096-1257

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