Tryptophan indole N-15-H-1 signals are well separated in nuclear magnetic resonance(NMR) spectra of proteins. Assignment of the indole N-15-H-1 signals therefore enables one to obtain site-specific information on complex proteins in supramacromolecular systems, even when extensive assignment of backbone N-15-H-1 resonances is challenging. Here we exploit the unique indole N-15-H-1 chemical shift by introducing extrinsic tryptophan reporter residues at judiciously chosen locations in a membrane protein for increased coverage of structure and function by NMR. We demonstrate this approach with three variants of the human A(2A) adenosine receptor (A(2A)AR), a class A G protein-coupled receptor, each containing a single extrinsic tryptophan near the receptor intracellular surface, in helix V, VI, or VII, respectively. We show that the native A(2A)AR global protein fold and ligand binding activity are preserved in these A(2A)AR variants. The indole N-15-H-1 signals from the extrinsic tryptophan reporter residues show different responses to variable efficacy of drugs bound to the receptor orthosteric cavity, and the indole N-15-H-1 chemical shift of the tryptophan introduced at the intracellular end of helix VI is sensitive to conformational changes resulting from interactions with a polypeptide from the carboxy terminus of the G alpha(s) intracellular partner protein. Introducing extrinsic tryptophans into proteins in complex supramolecular systems thus opens new avenues for NMR investigations in solution.