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A rational design strategy for protein hormone superagonists

Nature Biotechnology volume 16, pages 871–875 (1998)Cite this article

Abstract

By combining evolutionary considerations, sequence comparisons and homology modeling we have designed recombinant human thyroid-stimulating hormone (hTSH) analogs with increased receptor binding and activity. The introduction of seven basic residues into the peripheral loops of hTSH resulted in up to a 50,000-fold increase in receptor binding affinity and 1300-fold increase in intrinsic activity. Such analogs are not only of potential clinical interest but can be tools to explore molecular aspects of conventional as well as nonclassical actions of glycoprotein hormones. These design strategies should be applicable to the development of novel analogs of other related hormones and growth factors with a variety of therapeutic and basic science applications, particularly for proteins that have undergone evolutionary decrease in bioactivity.

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Author notes

  1. Mathis Grossmann

    Present address: Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Victoria, 3050, Australia

  2. Mariusz W. Szkudlinski: Corresponding author (e-mail: szkudlin@umbi.umd.edu)

Authors and Affiliations

  1. Laboratory of Molecular Endocrinology, Department of Medicine, University of Maryland School of Medicine and the Institute of Human Virology, Medical Biotechnology Center, UMB1, Baltimore, MD, 21201-1734

    Holger Leitolf, Bruce D. Weintraub & Mariusz W. Szkudlinski

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  1. Mathis Grossmann
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  4. Mariusz W. Szkudlinski
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Grossmann, M., Leitolf, H., Weintraub, B. et al. A rational design strategy for protein hormone superagonists. Nat Biotechnol 16, 871–875 (1998). https://doi.org/10.1038/nbt0998-871

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