In this communication, we disclose a generalizable strategy for developing agents with regulable protein-binding ability. In particular, a responsive DNA-small molecule chimera (DC) 1 consisting of two synthetic protein-binding arms and a core oligonucleotide (ODN) domain is discussed. DC 1 can be cycled from a bidentate intramolecular quadruplex form to a monodentate duplex structure, via addition of external ODN stimuli. Importantly, these distinct secondary structures of 1 lead to significantly different protein-binding abilities, with the bidentate conformation showing a 20-fold enhancement (with a 0.8 mu M dissociation constant, K-d) in trypsin-binding potency.