We detail the Structure and dynamics of a synthetic peptide corresponding to transmembrane helix 6 (TMH6) of human cannabinoid receptor-2 (hCB2) in biomembrane-mimetic environments. The peptide's NMR structural biology is characterized by two alpha-helical domains bridged by a flexible, nonhelical hinge region containing a highly-conserved CWFP motif with an environmentally sensitive, Pro-based conformational switch. Buried within the peptide's flexible region, W-258 may hydrogen-bond with L-255 to help stabilize the Pro-kinked hCB2 TMH6 structure and position C-257 advantageously for interaction with agonist ligands. These characteristics of hCB2 TMH6 are potential Structural features of ligand-induced hCB2 activation in vivo. (C) 2009 Elsevier Inc. All rights reserved.