Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1993-09-29
1996-04-09
Saunders, David
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 78, 436501, 436537, G01N 33542, G01N 33566
Patent
active
055061079
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of polypeptide ligand and receptor interactions. In particular, it relates to the field of selecting and screening antagonists and agonists for polypeptide ligands.
2. Description of the Background Art
Ligand induced receptor oligomerization has been proposed as a mechanism of signal transduction for the large family of tyrosine kinase receptors that contain an extracellular ligand binding domain (for reviews see Yarden, Y., et al., Ann. Rev. Biochem 57:443-478 (1988); Ullrich, A., et al., Cell 61:203-212 [1990]). In these models binding of one hormone molecule (or subunit) (H) per receptor (R) is thought to induce formation of an H.sub.2 R.sub.2 complex. For example, crosslinking and non-dissociating electrophoretic studies suggest that epidermal growth factor (EGF) promotes dimerization of the EGF receptor followed by receptor autophosphorylation and activation of the intracellular tyrosine kinase (Shector, Y., et al., Nature 278:835-838 (1979); Schreiber, A. B., et al., J. Biol. Chem., 258:846-853 (1983); Yarden, Y., et al., Biochemistry, 26:1434-1442 (1987); Yarden, Y., et al., Biochemistry 26:1443-1451 (1987). Studies of other tyrosine kinase receptors including the insulin receptor (Kahn, C. R., et al., Proc. Natl. Acad. Sci. U.S.A. 75:4209-4213 (1978); Kubar J., et al., Biochemistry 28:1086-1093 (1989): Heffetz, D., et al., J. Biol. Chem. 261:889-894 (1986), platelet derived growth factor (PDGF) receptor (Heldin, C. H., et al., J. Biol. Chem. 264:8905-8912 (1989); Hammacher, A., et al., EMBO J. 8:2489-2495 (1989); Seifert, R. A., et al., J. Biol., Chem. 264:8771-8778 (1989)) and insulin-like growth factor (IGF-I) receptor (Ikari, N., et al., Mol. Endocrinol. 2:831-837), indicate that oligomerization of the receptor is tightly coupled to the biological effect. Other groups have recently crystallized a polypeptide hormone in complex with its extracellular binding domain (Lambert, G., et al., J. Biol. Chem. 264:12730-12736 (1989); Gunther, N., et al., J. Biol. Chem. 265:22082-22085 (1990)). However, more detailed analyses of the structural perturbations and requirements for ligand induced changes in these or other receptors have been hampered because of the complexities of these membrane associated systems and the lack of suitable quantities of highly purified natural or recombinant receptors.
When purified receptors were available the assay procedures were often structured so that the nature of the hormone-receptor complex was not recognized. In U.S. Pat. No. 5,057,417, hGH binding assays were conducted using .sup.125 I-hGH competition with cold hGH for binding to the extracellular domain of recombinant hGH receptor (hGHbp), or hGH binding protein; the resulting complex was treated with antibody to the hGHbp, plus polyethylene glycol, to precipitate the complex formed. These immunoprecipitation assays suggested that hGH formed a 1:1 complex with hGHbp. This immunoprecipitation assay correctly detected the amount of .sup.125 I-hGH bound, but it incorrectly indicated a 1:1 molar ratio.
Various solid phase assays for hGH receptor and binding protein have been used. Such assays detected the amount of hGH bound but not the molar ratio of hGH to receptor. Binding assays with solid phase or with membrane fractions containing hGH receptor were not suitable for determining the molar ratio of hGH to receptor due to an inability to detect the total amount of active receptor and/or the amount of endogenous hGH bound. Based upon earlier work, such as with EGF, the art assumed the hGH-receptor complex would be an H.sub.2 R.sub.2 tetramer.
The hGH receptor cloned from human liver (Leung, D. W. et al., Nature, 330:537 (1987)) has a single extracellular domain (.about.28 kD), a transmembrane segment, and an intracellular domain (.about.30 kD) that is not homologous to any known tyrosine kinase or other protein. Nonetheless, the extracellular portion of the hGH receptor is structurally related to the extracellular domains of the
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Ashkenazi, et a
Cunningham Brian C.
DeVos Abraham M.
Mulkerrin Michael G.
Ultsch Mark
Wells James A.
Genentech Inc.
Haliday Emily M.
Saunders David
Terlizzi Laura
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