**7. Conclusions**

Because X-ray crystal structures are used frequently for drug design projects, it is critical to identify any issues with these structures, such as crystal packing effects and to evaluate how consistent these structures are with the body of structural information in the literature for a given receptor, such as mutation, cross-linking and NMR studies. Results presented in this chapter show that crystal packing issues impact both of the CB1 inactive state crystal structures and the activated state CB1 crystal structures. Impacts include N-terminus insertions deep into the binding pocket seen in the CB1 inactive state structures, as well as, TMH1 and TMH2 bending into the binding pocket seen in the activated state structures. Not surprisingly, we find here that the CB1 structures have important inconsistencies with mutation data, particularly in their TMH1-2-3 regions. In addition, the CB1 crystal structures do not capture the movement of W6.48 during receptor activation, or the existence of a ligand portal in the activated state, however, X-ray structures by their very nature will not capture all transient changes. In conclusion, then, the CB1 crystal structures are an important contribution to the drug design field, but revisions are advisable before these structures are used for structure-based drug discovery.
