DOI: 10.1126/science.256.5064.1677. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

10.1126/science.256.5064.1677

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially—a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

Bibliography

Fuh, G., Cunningham, B. C., Fukunaga, R., Nagata, S., Goeddel, D. V., & Wells, J. A. (1992). Rational Design of Potent Antagonists to the Human Growth Hormone Receptor. Science, 256(5064), 1677â1680.

Authors 6

Germaine Fuh (first)
Brian C. Cunningham (additional)
Rikiro Fukunaga (additional)
Shigekazu Nagata (additional)
David V. Goeddel (additional)
James A. Wells (additional)

References 23 Referenced 491

BARNARD, R, EVIDENCE FROM THE USE OF MONOCLONAL-ANTIBODY PROBES FOR STRUCTURAL HETEROGENEITY OF THE GROWTH-HORMONE RECEPTOR, BIOCHEMICAL JOURNAL 231: 459 (1985). (10.1042/bj2310459) / BIOCHEMICAL JOURNAL (1985)
BAS, S.H., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 88: 4498 (1991). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1991)
BAZAN, J.F., STRUCTURAL DESIGN AND MOLECULAR EVOLUTION OF A CYTOKINE RECEPTOR SUPERFAMILY, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 87: 6934 (1990). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1990)
CHEN, W.Y., GLYCINE-119 OF BOVINE GROWTH-HORMONE IS CRITICAL FOR GROWTH-PROMOTING ACTIVITY, MOLECULAR ENDOCRINOLOGY 5: 1845 (1991). (10.1210/mend-5-12-1845) / MOLECULAR ENDOCRINOLOGY (1991)
COSMAN, D, A NEW CYTOKINE RECEPTOR SUPERFAMILY, TRENDS IN BIOCHEMICAL SCIENCES 15: 265 (1990). (10.1016/0968-0004(90)90051-C) / TRENDS IN BIOCHEMICAL SCIENCES (1990)
CUNNINGHAM, B.C., RATIONAL DESIGN OF RECEPTOR-SPECIFIC VARIANTS OF HUMAN GROWTH-HORMONE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 88: 3407 (1991). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1991)
10.1126/science.2471267
10.1126/science.2321008
10.1126/science.1948064
10.1126/science.1549776
FROHMAN, L.A., CLINICAL REVIEW .22. THERAPEUTIC OPTIONS IN ACROMEGALY, JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM 72: 1175 (1991). (10.1210/jcem-72-6-1175) / JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM (1991)
10.1016/S0021-9258(19)39741-8
FUH G unpublished data.
FUKUNAGA, R, EXPRESSION CLONING OF A RECEPTOR FOR MURINE GRANULOCYTE COLONY-STIMULATING FACTOR, CELL 61: 341 (1990). (10.1016/0092-8674(90)90814-U) / CELL (1990)
FUKUNAGA, R, FUNCTIONAL DOMAINS OF THE GRANULOCYTE COLONY-STIMULATING FACTOR RECEPTOR, EMBO JOURNAL 10: 2855 (1991). (10.1002/j.1460-2075.1991.tb07835.x) / EMBO JOURNAL (1991)
FUKUNAGA, R, PURIFICATION AND CHARACTERIZATION OF THE RECEPTOR FOR MURINE GRANULOCYTE COLONY-STIMULATING FACTOR, JOURNAL OF BIOLOGICAL CHEMISTRY 265: 14008 (1990). (10.1016/S0021-9258(18)77449-8) / JOURNAL OF BIOLOGICAL CHEMISTRY (1990)
Higuchi, R., PCR Protocols: A Guide to Methods and Applications: 177 (1989). / PCR Protocols: A Guide to Methods and Applications (1989)
ISHIZAKAIKEDA E unpublished data.
10.1016/0076-6879(87)54085-X
10.1038/330537a0
MELMED, S, MEDICAL PROGRESS - ACROMEGALY, NEW ENGLAND JOURNAL OF MEDICINE 322: 966 (1990). (10.1056/NEJM199004053221405) / NEW ENGLAND JOURNAL OF MEDICINE (1990)
PATTHY, L, HOMOLOGY OF A DOMAIN OF THE GROWTH-HORMONE PROLACTIN RECEPTOR FAMILY WITH TYPE-III MODULES OF FIBRONECTIN, CELL 61: 13 (1990). (10.1016/0092-8674(90)90208-V) / CELL (1990)
Wells, J. A., Recent Progress in Hormone Research 48: 253 (1993). / Recent Progress in Hormone Research (1993)

Dates

Type	When
Created	18 years, 10 months ago (Oct. 5, 2006, 7:03 p.m.)
Deposited	1 year, 7 months ago (Jan. 12, 2024, 6:29 p.m.)
Indexed	3 weeks, 3 days ago (Aug. 5, 2025, 8:38 a.m.)
Issued	33 years, 2 months ago (June 19, 1992)
Published	33 years, 2 months ago (June 19, 1992)
Published Print	33 years, 2 months ago (June 19, 1992)

Funders 0

None

BibTeX

@article{Fuh_1992, title={Rational Design of Potent Antagonists to the Human Growth Hormone Receptor}, volume={256}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.256.5064.1677}, DOI={10.1126/science.256.5064.1677}, number={5064}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Fuh, Germaine and Cunningham, Brian C. and Fukunaga, Rikiro and Nagata, Shigekazu and Goeddel, David V. and Wells, James A.}, year={1992}, month=jun, pages={1677–1680} }

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