Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4)

K. Nagata, Daisuke Kohda, H. Hatanaka, S. Ichikawa, S. Matsuda, T. Yamamoto, A. Suzuki, F. Inagaki

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

p185(erB-2) and p180(erB-4) are epidermal growth factor (EGF) receptor-like tyrosine kinases, whose co-expression is observed in many breast carcinomas. Heregulins (HRGs), which contain an immunoglobulin unit and an EGF-like domain, bind to p180(erB-4) and activate p180(erB-4) and p185(erbB-2) through transphosphorylation or receptor heterodimerization. The EGF-like domain is sufficient for the activation. Despite the sequence similarity, no cross activity is seen between the p180(erbB-4) ligands (HRGs) and the p170(erbB-1) ligands [EGF and transforming growth factor (TGF)-α]. To investigate the structural basis of receptor specificity, we have determined the solution structure of the EGF-like domain of HRG-α by two-dimensional 1H nuclear magnetic resonance spectroscopy and simulated annealing calculations. Though its main-chain fold is similar to those of EGF and TGF-α, distinctive structural features are observed on the molecular surface including an ionic cluster and hydrophobic patches, which afford HRG-α the specific affinity for p180(erbB-4). The structure should provide a basis for the structure - activity relationship of HRGs and for the design of drugs which prevent progression of breast cancer.

Original languageEnglish
Pages (from-to)3517-3523
Number of pages7
JournalEMBO Journal
Volume13
Issue number15
Publication statusPublished - Jan 1 1994

Fingerprint

Neuregulin-1
Epidermal Growth Factor
Ligands
Transforming Growth Factors
Breast Neoplasms
Drug Design
Structure-Activity Relationship
Simulated annealing
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Nuclear magnetic resonance spectroscopy
Immunoglobulins
Magnetic Resonance Spectroscopy
Chemical activation
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Nagata, K., Kohda, D., Hatanaka, H., Ichikawa, S., Matsuda, S., Yamamoto, T., ... Inagaki, F. (1994). Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4). EMBO Journal, 13(15), 3517-3523.

Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4). / Nagata, K.; Kohda, Daisuke; Hatanaka, H.; Ichikawa, S.; Matsuda, S.; Yamamoto, T.; Suzuki, A.; Inagaki, F.

In: EMBO Journal, Vol. 13, No. 15, 01.01.1994, p. 3517-3523.

Research output: Contribution to journalArticle

Nagata, K, Kohda, D, Hatanaka, H, Ichikawa, S, Matsuda, S, Yamamoto, T, Suzuki, A & Inagaki, F 1994, 'Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4)', EMBO Journal, vol. 13, no. 15, pp. 3517-3523.
Nagata K, Kohda D, Hatanaka H, Ichikawa S, Matsuda S, Yamamoto T et al. Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4). EMBO Journal. 1994 Jan 1;13(15):3517-3523.
Nagata, K. ; Kohda, Daisuke ; Hatanaka, H. ; Ichikawa, S. ; Matsuda, S. ; Yamamoto, T. ; Suzuki, A. ; Inagaki, F. / Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4). In: EMBO Journal. 1994 ; Vol. 13, No. 15. pp. 3517-3523.
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