kinase domain although without distinction between the inactive and active form of the ligand finally they provide evidence that engineered proteins derived from the ipt region and sema domain of met are capable of neutralizing the pro invasive activity of hgf both in vitro and in vivo it has been known for long time that hgf is a bivalent factor early protein engineering studies identified a high affinity met binding site in the n domain and first kringle of hgf subsequently combined biochemical and biological analysis demonstrated that the hgf serine protease like domain u03b2 chain while not necessary for binding plays a key role in mediating receptor activation more recently detailed crystallographic and mutagenesis data have thoroughly characterized both structurally and functionally the low affinity met binding site on the u03b2 chain of hgf and its interaction with the sema domain of met the interface between the u03b1 chain of hgf and met had remained however elusive small angle x ray scattering and cryo electron microscopy studies suggested the presence of contacts among the n terminal and first kringle domain of hgf and the sema domain of met however plasmon resonance analysis revealed that this interaction has a very low affinity about 2 times lower than that of hgf u03b2 for sema and 100 times lower than that of hgf u03b1 for the intact receptor since this weak interaction cannot account per se for the tight bond between hgf and met the high affinity hgf binding site on met had still to be identified the results presented here contribute to fill this gap and suggest that this long sought after hgf binding site lies in the ipt region of met and more precisely in the last two immunoglobulin like domains close to the cell membrane.