Despite the pivotal role GPCRs play in cellular signaling, it is only in the recent years that structural biology has begun to elucidate how GPCRs function and to provide a platform for structure-based drug design. It is postulated that GPCR activation involves the movement of transmembrane helices. The finding that many residues, which have been shown to be critical for receptor activation and are highly conserved among different GPCRs, are clustered in particular positions of transmembrane helices suggests that activation of GPCRs may involve common molecular mechanisms. In particular, phenylalanine 6.44, located in the upper half of TMVI, is highly conserved among almost all GPCRs. We generated Phe 2436.44 Ala/Ser mutants of histamine H2 receptor and found that while the substitutions do not affect receptor expression or ligand signaling, are able to specifically alter cimetidine and ranitidine mechanisms of action from simply inactivating the receptor to produce a ligand-induced G-protein sequestering conformation, that interferes with the signaling of β2-adrenoceptor. Taking advantage of the cubic ternary complex model, and mathematically modeling our results, we hypothesize that this alteration in ligand mechanism of action is consequence of a change in ligand-induced conformational rearrangement of receptor and its effect on G-protein coupling. Our results show that receptor point mutations can not only alter receptor behavior, as shown for activating/inactivating mutations, but also can have more subtle effects changing ligand mechanism of action.