Modification of a receptor-binding surface of epidermal growth factor (EGF): analogs with enhanced receptor affinity at low pH or at neutrality

Protein Eng. 1998 Jun;11(6):473-80. doi: 10.1093/protein/11.6.473.


Six mutants of human epidermal growth factor (EGF), which carry single point substitutions within a surface patch proposed to juxtapose the bound receptor, were prepared and characterized for receptor affinity and mitogenicity. Receptor affinities relative to EGF are G12Q > H16D > Y13W > Q43A approximately = H16A approximately = EGF >> L15A. Notably, the reduced receptor affinity of mutant L15A indicates that Leu15 probably contributes substantially to receptor binding whereas unaltered receptor affinities observed for analogs H16A and Q43A indicate that neither His16 nor Gln43 contributes significantly to this interaction. On the other hand, the observed enhanced receptor affinities of analogs G12Q, Y13W and H16D highlight surface loci where additional productive receptor-binding contacts can be introduced. Interestingly, at acidic pH analog H16A reveals substantially greater receptor affinity than that of EGF, a property which may offer enhanced therapeutic utility in acidic environments in vivo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Binding Sites
  • Epidermal Growth Factor / chemistry*
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism*
  • Genetic Vectors
  • Humans
  • Hydrogen-Ion Concentration
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Structure-Activity Relationship


  • Epidermal Growth Factor
  • ErbB Receptors