Figure 1. The human Met signalling cascade and RaPID selection.

(a) When human HGF (hHGF) binds to the Met ectodomain, it forms a 2:2 dimerization complex, bringing intracellular tyrosine kinase domains into close proximity and inducing trans-phosphorylation. Met activation transduces major signals through the adaptor protein Gab1. Activation of downstream cytoplasmic kinases such as Akt and Erk1/2 (mitogen-activated protein kinase (MAPK)) eventually promote cellular phenotypic changes. (b) Using the RaPID system, we can select artificial macrocycles fused to the respective mRNAs against a target: in this case, the human Met ectodomain. During the selection process, binding species are enriched from an initial library of 10¹² unique members of macrocycle–mRNA fusions. PCR amplification of cDNAs and cDNA transcription and translation can be repeated until the active species dominates (Supplementary Fig. 1).