title: NMR solution structure of human cannabinoid receptor-1 helix 7/8 peptide: candidate electrostatic interactions and microdomain formation.
abstract: We report the NMR solution structure of a synthetic 40-mer (T(377)-E(416)) that encompasses human cannabinoid receptor-1 (hCB1) transmembrane helix 7 (TMH7) and helix 8 (H8) [hCB1(TMH7/H8)] in 30% trifluoroethanol/H(2)O. Structural features include, from the peptide's amino terminus, a hydrophobic alpha-helix (TMH7); a loop-like, 11 residue segment featuring a pronounced Pro-kink within the conserved NPxxY motif; a short amphipathic alpha-helix (H8) orthogonal to TMH7 with cationic and hydrophobic amino-acid clusters; and an unstructured C-terminal end. The hCB1(TMH7/H8) NMR solution structure suggests multiple electrostatic amino-acid interactions, including an intrahelical H8 salt bridge and a hydrogen-bond network involving the peptide's loop-like region. Potential cation-pi and cation-phenolic OH interactions between Y(397) in the TMH7 NPxxY motif and R(405) in H8 are identified as candidate structural forces promoting interhelical microdomain formation. This microdomain may function as a flexible molecular hinge during ligand-induced hCB1 conformer transitions.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Center for Drug Discovery, Boston, MA 02115-5000, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Tyukhtenko
authors.forename: Elvis K
authors.initials: EK
authors.lastname: Tiburu
authors.forename: Lalit
authors.initials: L
authors.lastname: Deshmukh
authors.forename: Olga
authors.initials: O
authors.lastname: Vinogradova
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D010455:Peptides; D043884:Receptor, Cannabinoid, CB1