C-Terminus

The C-terminus is the end of a peptide chain at which the last residue's alpha-carboxyl group is not bonded to a further amino acid. Sequences are written and numbered from the N-terminus to the C-terminus by universal convention, so the C-terminus is where a written sequence stops, and ribosomal synthesis proceeds the same way. Ionised at physiological pH, an unmodified C-terminus contributes a negative charge, one reason so many natural peptides arrive amidated.

Which end a peptide's function lives at is often surprisingly clean-cut. For the class B receptors binding GLP-1, GIP and GHRH, the two-domain model assigns affinity largely to the C-terminal region, which docks into the receptor's extracellular domain, and activation to the N-terminal residues, which enter the transmembrane bundle. Exendin-4 illustrates it: the nine-residue C-terminal extension absent from GLP-1 contributes substantially to binding, and the truncated fragment exendin(9-39) retains enough of it to act as an antagonist.

That division tells you what a truncation costs. Losing C-terminal residues typically bleeds affinity while leaving intrinsic activity intact, giving a weaker agonist; losing the first few N-terminal residues destroys activation and can convert an agonist into an antagonist. The same logic guides where a modification is hung, since a fatty acid placed near the activating end is far likelier to interfere.

Two mistakes cluster here. One is misreading sequence direction, which matters because a peptide and its reversed sequence are different molecules sharing a composition and a mass. The other is assuming a fragment name implies the parent's activity: a designation such as a 1-29 or 7-36 fragment states only which residues are present, and whether it is a full agonist, a partial agonist or inert the name does not answer.