Structural studies of receptor tyrosine kinases

S. R. Hubbard, M. Mohammadi, J. Schlessinger, Lei Wei, L. Ellis, W. A. Hendrickson

Research output: Contribution to journalArticle

Abstract

Many important cellular signaling cascades are initiated at the cell surface by the binding of a polypeptide ligand to a transmembrane receptor possessing intrinsic tyrosine kinase activity. Receptors of this type include, among others, the insulin receptor and the epidermal, fibroblast and platelet-derived growth factor receptors. We have previously determined the crystal structure of the tyrosine kinase domain of the human insulin receptor. This structure revealed a novel autoinhibitory mechanism whereby one of the activation loop tyrosines, which is autophosphorylated in response to insulin, is bound in the active site, precluding both substrate and ATP binding. This structure and the structure of the cAMP-dependent serine/threonine kinase provide a basis for understanding kinase substrate selectivity (serine/threonine vs. tyrosine). We are pursuing crystallographic studies of the phosphorylated, activated form of the insulin receptor kinase to elucidate the role of phosphorylation in insulin receptor activation. We have determined the crystal structure of a second receptor tyrosine kinase domain, that of fibroblast growth factor receptor 1. Although the overall structure of this tyrosine kinase is quite similar to the structure of the insulin receptor kinase, a difference in the conformation of the (non-phosphorylated) activation loop provides evidence for another mechanism of tyrosine kinase autoinhibition.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number6
StatePublished - 1996
Externally publishedYes

Fingerprint

Insulin Receptor
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
tyrosine
phosphotransferases (kinases)
receptors
Phosphotransferases
Chemical activation
Tyrosine
Crystal structure
Receptor, Fibroblast Growth Factor, Type 1
Cell signaling
Platelet-Derived Growth Factor Receptors
Phosphorylation
Protein-Serine-Threonine Kinases
Substrates
Threonine
Fibroblasts
Serine
crystal structure

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Hubbard, S. R., Mohammadi, M., Schlessinger, J., Wei, L., Ellis, L., & Hendrickson, W. A. (1996). Structural studies of receptor tyrosine kinases. FASEB Journal, 10(6).

Structural studies of receptor tyrosine kinases. / Hubbard, S. R.; Mohammadi, M.; Schlessinger, J.; Wei, Lei; Ellis, L.; Hendrickson, W. A.

In: FASEB Journal, Vol. 10, No. 6, 1996.

Research output: Contribution to journalArticle

Hubbard, SR, Mohammadi, M, Schlessinger, J, Wei, L, Ellis, L & Hendrickson, WA 1996, 'Structural studies of receptor tyrosine kinases', FASEB Journal, vol. 10, no. 6.
Hubbard SR, Mohammadi M, Schlessinger J, Wei L, Ellis L, Hendrickson WA. Structural studies of receptor tyrosine kinases. FASEB Journal. 1996;10(6).
Hubbard, S. R. ; Mohammadi, M. ; Schlessinger, J. ; Wei, Lei ; Ellis, L. ; Hendrickson, W. A. / Structural studies of receptor tyrosine kinases. In: FASEB Journal. 1996 ; Vol. 10, No. 6.
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