MODIFICATION OF A RECEPTOR-BINDING SURFACE OF EPIDERMAL GROWTH-FACTOR(EGF) - ANALOGS WITH ENHANCED RECEPTOR AFFINITY AT LOW PH OR AT NEUTRALITY

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 approximate to H16A approximate to EGF >> L15A. Notably, the reduced receptor affinity of mutant L15A indicates that Leu15 pro bably contributes substantially to receptor binding whereas unaltered receptor affinities observed for analogs H16A and Q43A indicate that n either His16 nor Gln43 contributes significantly to this interaction. On the other hand, the observed enhanced receptor affinities of analog s G12Q, Y13W and H16D highlight surface loci where additional producti ve receptor-binding contacts can be introduced, Interestingly, at acid ic 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.