doi: 10.3410/B1-77.
Bitopic ligands: all-in-one orthosteric and allosteric
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- PMID:20948611
- PMCID: PMC2948289
- DOI: 10.3410/B1-77
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Bitopic ligands: all-in-one orthosteric and allosteric
Maud Kamal et al. F1000 Biol Rep..
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Abstract
Natural ligands of G-protein-coupled receptors interact with the orthosteric ligand binding site, as do most of the classical synthetic ligands. The discovery of ligands targeting different, allosteric binding sites considerably expanded the repertoire of G-protein-coupled receptor ligands. More recently, bitopic ligands have been described that target both orthosteric and allosteric sites at the same time.
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(a) An allosteric ligand may modulate binding (1) and signaling (2) of orthosteric ligands or (3) induce signal transduction by its own (allosteric agonists) (adapted from Langmead and Christopoulos [3]).(b,c) Comparison of different binding modes of orthosteric (red circle) and allosteric (red triangle) ligands as monovalent ligands(b) or bivalent bitopic ligands(c). Binding of orthosteric ligands induces Signal 1, which can be modulated by allosteric ligands binding to sites that are close to or distant from the orthosteric binding site, generating Signal 1* or Signal 1**. Alternatively, the signal generated by the orthosteric ligand in one protomer can be allosterically modulated by the other protomer within a GPCR dimer, generating Signal 1***. Allosteric agonists can induce signaling by their own in the absence of orthosteric ligands (Signal 2). Signals 1*, 1**, and 1*** can also be generated by bitopic ligands. In addition, bitopic ligands could induce signals (Signals 1’, 1’’, and 1’’’) that are specific for these ligands and not observed upon simultaneous stimulation with monovalent orthosteric and allosteric ligands.
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