Over the last few years the importance of the intracellular C-terminus in the signaling of G-protein coupled receptors (GPCR) has become increasingly evident. In an effort to provide a structural framework for biological function, we have determined the conformation of the C-terminus of the bradykinin (BK) B2 receptor. Using a uniformly 15N- and 13C-enriched sample of the BKB2 receptor [309-366], NMR results clearly define three alpha-helices lying on the zwitterionic surface of the dodecylphosphocholine. The proximal helix consisting of residues 311-326 was previously predicted based on homology modeling with rhodopsin. This corresponds to what is often called helix-8 of the GPCRs. The two distal helices, residues 333-345 and 348-363, are clearly borne out by the NMR data. The functional importance of these secondary structural elements was probed by determination of the signaling properties (inositol phosphate formation) of mutant BKB2 receptors lacking the domains (deletion mutants) or containing the corresponding region from the related GPCR, angiotensin II AT1a (chimera receptors). We demonstrate that the regions between the helices (residues 327-333 and 346-347) can be exchanged without loss of signaling. In contrast, modification of the three helices, particularly the hydroxyl-containing residues, has drastic effects on the signaling profile of the BKB2 receptor. By coupling of the structural features with the functional data, the molecular mechanisms of signaling by the BKB2 receptor are beginning to be established.