Fig. 1

Structure of c-Met and binding sites for c-Met monoclonal antibody and small molecule inhibitors. c-Met is a heterodimer linked by an extracellular α chain and a transmembrane β chain. The β chain has a SEMA domain, a PSI domain, four IPT domains, a transmembrane domain, a juxtamembrane domain, a tyrosine kinase domain, and a C-terminal tail region. HGF is a heterodimer consisting of an α chain and a β chain linked via a disulfide bond, and forming six domains: the α chain contains a N-terminal hairpin domain and four Kringle domains and the β chain forms a serine protease analog domain lacking catalytic activity. The SEMA domain and the PSI domain in c-Met bind the β chain of HGF. The small molecule inhibitor PF-2341066 binds the TK domain of c-Met at Tyr312A, Lys345A, Pro317A, whereas the small molecule inhibitor ARQ197 forms a complex with the TK domain of c-Met at Pro1158A, Met1160A, Phe1123A, and onartuzumab forms a complex with the Sema-PSI domain of c-Met at Leu43B