Autocrine based selections from intracellular combinatorial antibody and peptide libraries have proven to be a powerful method for selection of agonists and identification of new therapeutic targets. However, success requires a case-by-case construction of a robust selection system which is a process that can be time consuming and expensive. Here we report a general system that takes advantage of the chemical rate acceleration caused by approximation of a membrane tethered ligand and its receptor. The system uses an artificial signal transduction and is, thus, agnostic to the endogenous signal transduction of the receptor-ligand system. This method allows analysis of receptor-ligand interactions and selection of molecules from large libraries that interact with receptors when they are in their natural milieu. (C) 2014 Elsevier Inc. All rights reserved.