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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the structure. A molecule that triggers this change is known as a modulator.

Two models are often used to explain cooperativity in multimeric proteins: the concerted and the sequential model. The concerted model, also known as the all-or-none model, hypothesizes that all the subunits of a multimeric protein switch simultaneously between the “on” and “off” conformations. In the “on” form, the binding sites have a high affinity for their respective ligands, and in the “off” form, the binding sites have a low affinity. When a ligand binds to any one of the subunits, it promotes the conversion to the high-affinity form, simultaneously changing the conformation of all other binding sites of the protein. Although a ligand can bind to either form, it is easier for it to bind when in the high-affinity form.

The sequential model assumes that each subunit of a multimeric protein can exist independently in an “on” or “off” conformation, that is in either the low or high-affinity form, regardless of the state of the other subunits. Binding of a ligand to a subunit changes the equilibrium between the low and high-affinity forms such that it is more likely for the subunit to be in high-affinity form. Additionally, a ligand binding on one subunit shifts the equilibrium for the other subunits in the protein. This increases the likelihood that once one ligand is bound, another ligand will bind to a different subunit. This cooperativity increases the sensitivity of the protein to ligand concentration. A ligand binding at a single site can change the affinity on the entire protein molecule, thereby enabling a rapid response at low concentrations.

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