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Unexpected non-apparent and hidden allosteric-binding sites are non-classical and non-apparent allosteric centers in 3-D X-ray protein structures until orthosteric or allosteric ligands bind to them. The orthosteric center of one protomer that modulates binding centers of the other protomers within an oligomer is also an unexpected allosteric site. Furthermore, another partner protein can also produce these effects, acting as an unexpected allosteric modulator. This review summarizes both classical and non-classical allosterism. The authors focus on G protein-coupled receptor (GPCR) oligomers as a paradigm of allosteric molecules. Moreover, they show several examples of unexpected allosteric sites such as hidden allosteric sites in a protomer that appear after the interaction with other molecules and the allosterism exerted between orthosteric sites within GPCR oligomer, emphasizing on the allosteric modulations that can occur between binding sites. The study of these new non-classical allosteric sites will expand the diversity of allosteric control on the function of orthosteric sites within proteins, whether GPCRs or other receptors, enzymes, or transporters. Moreover, the design of new drugs targeting these hidden allosteric sites or already known orthosteric sites acting as allosteric sites in protein homo- or hetero-oligomers will increase the therapeutic potential of allosterism.

Unmasking allosteric-binding sites: novel targets for GPCR drug discovery