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Science 17 January 1992:
Vol. 255. no. 5042, pp. 306 - 312
DOI: 10.1126/science.1549776
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Articles

Science, Vol 255, Issue 5042, 306-312
Copyright © 1992 by American Association for the Advancement of Science

articles

Human growth hormone and extracellular domain of its receptor: crystal structure of the complex

AM de Vos, M Ultsch, and AA Kossiakoff

Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.

Binding of human growth hormone (hGH) to its receptor is required for regulation of normal human growth and development. Examination of the 2.8 angstrom crystal structure of the complex between the hormone and the extracellular domain of its receptor (hGHbp) showed that the complex consists of one molecule of growth hormone per two molecules of receptor. The hormone is a four-helix bundle with an unusual topology. The binding protein contains two distinct domains, similar in some respects to immunoglobulin domains. The relative orientation of these domains differs from that found between constant and variable domains in immunoglobulin Fab fragments. Both hGHbp domains contribute residues that participate in hGH binding. In the complex both receptors donate essentially the same residues to interact with the hormone, even though the two binding sites on hGH have no structural similarity. Generally, the hormone-receptor interfaces match those identified by previous mutational analyses. In addition to the hormone-receptor interfaces, there is also a substantial contact surface between the carboxyl-terminal domains of the receptors. The relative extents of the contact areas support a sequential mechanism for dimerization that may be crucial for signal transduction.


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J. Biol. Chem. 278, 22868-22876
   Abstract »    Full Text »    PDF »
Real-time Kinetics of the Interaction between the Two Subunits, Escherichia coli Thioredoxin and Gene 5 Protein of Phage T7 DNA Polymerase.
N. C. Singha, A. Vlamis-Gardikas, and A. Holmgren (2003)
J. Biol. Chem. 278, 21421-21428
   Abstract »    Full Text »    PDF »
Dimerization and Signal Transduction of the Growth Hormone Receptor.
J. Gent, M. van den Eijnden, P. van Kerkhof, and G. J. Strous (2003)
Mol. Endocrinol. 17, 967-975
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Heterozygous Nonsense Mutation in Exon 3 of the Growth Hormone Receptor (GHR) in Severe GH Insensitivity (Laron Syndrome) and the Issue of the Origin and Function of the GHRd3 Isoform.
J. Pantel, J. Grulich-Henn, M. Bettendorf, C. J. Strasburger, U. Heinrich, and S. Amselem (2003)
J. Clin. Endocrinol. Metab. 88, 1705-1710
   Abstract »    Full Text »    PDF »
Natriuretic Peptide Receptor A Activation Stabilizes a Membrane-distal Dimer Interface.
A. De Lean, N. McNicoll, and J. Labrecque (2003)
J. Biol. Chem. 278, 11159-11166
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A Novel Functional Epitope Formed by Domains 1 and 4 of the Human Common beta -Subunit Is Involved in Receptor Activation by Granulocyte Macrophage Colony-stimulating Factor and Interleukin 5.
J. M. Murphy, S. C. Ford, U. M. Wiedemann, P. D. Carr, D. L. Ollis, and I. G. Young (2003)
J. Biol. Chem. 278, 10572-10577
   Abstract »    Full Text »    PDF »
Selective Binding and Oligomerization of the Murine Granulocyte Colony-stimulating Factor Receptor by a Low Molecular Weight, Nonpeptidyl Ligand.
M. L. Doyle, S.-S. Tian, S. G. Miller, L. Kessler, A. E. Baker, M. R. Brigham-Burke, S. B. Dillon, K. J. Duffy, R. M. Keenan, R. Lehr, et al. (2003)
J. Biol. Chem. 278, 9426-9434
   Abstract »    Full Text »    PDF »
Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization.
B. Bernat, G. Pal, M. Sun, and A. A. Kossiakoff (2003)
PNAS 100, 952-957
   Abstract »    Full Text »    PDF »
Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding. DETERMINATION OF EXTRACELLULAR DOMAIN STEM REGION CLEAVAGE SITE.
X. Wang, K. He, M. Gerhart, Y. Huang, J. Jiang, R. J. Paxton, S. Yang, C. Lu, R. K. Menon, R. A. Black, et al. (2002)
J. Biol. Chem. 277, 50510-50519
   Abstract »    Full Text »    PDF »
Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain.
J. N. Varghese, R. L. Moritz, M.-Z. Lou, A. van Donkelaar, H. Ji, N. Ivancic, K. M. Branson, N. E. Hall, and R. J. Simpson (2002)
PNAS 99, 15959-15964
   Abstract »    Full Text »    PDF »
Impact of Experimental Blockade of Peripheral Growth Hormone (GH) Receptors on the Kinetics of Endogenous and Exogenous GH Removal in Healthy Women and Men.
J. D. Veldhuis, M. Bidlingmaier, S. M. Anderson, W. S. Evans, Z. Wu, and C. J. Strasburger (2002)
J. Clin. Endocrinol. Metab. 87, 5737-5745
   Abstract »    Full Text »    PDF »
Exploring the potential of the monobody scaffold: effects of loop elongation on the stability of a fibronectin type III domain.
V. Batori, A. Koide, and S. Koide (2002)
Protein Eng. Des. Sel. 15, 1015-1020
   Abstract »    Full Text »    PDF »
Evidence for Plasticity and Structural Mimicry at the Immunoglobulin Light Chain-Protein L Interface.
M. Graille, S. Harrison, M. P. Crump, S. C. Findlow, N. G. Housden, B. H. Muller, N. Battail-Poirot, G. Sibai, B. J. Sutton, M. J. Taussig, et al. (2002)
J. Biol. Chem. 277, 47500-47506
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Subcloning, Expression, Purification, and Characterization of Recombinant Human Leptin-binding Domain.
Y. Sandowski, N. Raver, E. E. Gussakovsky, S. Shochat, O. Dym, O. Livnah, M. Rubinstein, R. Krishna, and A. Gertler (2002)
J. Biol. Chem. 277, 46304-46309
   Abstract »    Full Text »    PDF »
Prolonged Retention after Aggregation into Secretory Granules of Human R183H-Growth Hormone (GH), a Mutant that Causes Autosomal Dominant GH Deficiency Type II.
Y. L. Zhu, B. Conway-Campbell, M. J. Waters, and P. S. Dannies (2002)
Endocrinology 143, 4243-4248
   Abstract »    Full Text »    PDF »
Growth Hormone, Acting in Part through the Insulin-Like Growth Factor Axis, Rescues Developmental, But Not Metabolic, Activity in the Mammary Gland of Mice Expressing a Single Allele of the Prolactin Receptor.
G. J. Allan, E. Tonner, M. C. Barber, M. T. Travers, J. H. Shand, R. G. Vernon, P. A. Kelly, N. Binart, and D. J. Flint (2002)
Endocrinology 143, 4310-4319
   Abstract »    Full Text »    PDF »
Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication.
K. Tan, M. Duquette, J.-h. Liu, Y. Dong, R. Zhang, A. Joachimiak, J. Lawler, and J.-h. Wang (2002)
J. Cell Biol. 159, 373-382
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Oligomerization-dependent Association of the SAM Domains from Schizosaccharomyces pombe Byr2 and Ste4.
R. Ramachander, C. A. Kim, M. L. Phillips, C. D. Mackereth, C. D. Thanos, L. P. McIntosh, and J. U. Bowie (2002)
J. Biol. Chem. 277, 39585-39593
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Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly.
J. J. Kopchick, C. Parkinson, E. C. Stevens, and P. J. Trainer (2002)
Endocr. Rev. 23, 623-646
   Abstract »    Full Text »    PDF »
Characterization of a Novel and Functional Human Prolactin Receptor Isoform ({Delta}S1PRLr) Containing Only One Extracellular Fibronectin-Like Domain.
J. B. Kline, M. A. Rycyzyn, and C. V. Clevenger (2002)
Mol. Endocrinol. 16, 2310-2322
   Abstract »    Full Text »    PDF »
Cytokine and Cytokine Receptor Pleiotropy and Redundancy.
K. Ozaki and W. J. Leonard (2002)
J. Biol. Chem. 277, 29355-29358
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Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis.
J. Gent, P. van Kerkhof, M. Roza, G. Bu, and G. J. Strous (2002)
PNAS 99, 9858-9863
   Abstract »    Full Text »    PDF »


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