How do allosteric modulators differ from orthosteric ligands?

• A. Allosteric modulators bind at a different site than the endogenous ligand.
• B. Allosteric modulators bind only after receptor internalization.
• C. Allosteric modulators require covalent bonds.
• D. Allosteric modulators degrade the receptor.

Answer: (A)

Allosteric modulators bind at a site on the receptor that is different from where the endogenous ligand binds. Because they attach to a separate site, they don’t directly compete with the natural ligand for the same pocket. Instead, their binding changes the receptor’s shape or dynamics, which can make the receptor respond more strongly or more weakly to the endogenous ligand. This modulation can be positive (enhancing the effect) or negative (damping the effect), and many of these modulators require the endogenous ligand to be present to exert their influence, though some can have their own intrinsic activity.

In contrast, orthosteric ligands bind at the same site as the endogenous ligand and can directly activate the receptor or block the endogenous ligand by occupying that shared site. The other statements aren’t characteristic of allosteric modulators: they don’t need receptor internalization to work, they don’t require covalent bonds for binding, and they don’t typically degrade the receptor.