Novel Peptide Ligands of RGS4 from a Focused One-Bead, One-Compound Library

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65605/1/j.1747-0285.2008.00687.x.pd

Pharmacophore elements of the TIPP class of delta opioid receptor antagonists

A series of tri-and tetrapeptides sharing the amino-terminal dipeptide unit Tyr-Tic, found in the high-affinity delta opioid receptor antagonist Tyr-Tic-Phe-Phe (TIPP), was prepared and evaluated in receptor binding assays to explore the role(s) of the phenylalanine residues in positions 3 and 4. It was found that aromaticity of residues 3 and 4 is not required for high affinity, a lipophilic side chain in either location being sufficient, as evidenced by the high delta receptor binding affinities observed for the tetrapeptide Tyr-Tic-Ala-Leu and the tripeptide Tyr-Tic-Leu. These results support the suggestion of Temussi et al. [Biochem. Biophys. Res. Commun., 198 (1994) 933] that the aromatic side chain of the Tic residue corresponds to the aromatic side chain found in residues 3 or 4 in other delta-selective peptide series.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43172/1/10989_2004_Article_BF00126275.pd

Opioid receptor affinity and selectivity effects of second residue and carboxy terminal residue variation in a cyclic disulfide-containing opioid tetrapeptide

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74202/1/j.1399-3011.1991.tb00274.x.pd

Unveiling the Membrane-Binding Properties of N‑Terminal and C‑Terminal Regions of G Protein-Coupled Receptor Kinase 5 by Combined Optical Spectroscopies

G protein-coupled receptor kinase 5 (GRK5) is thought to associate with membranes in part via N- and C-terminal segments that are typically disordered in available high-resolution crystal structures. Herein we investigate the interactions of these regions with model cell membrane using combined sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy. It was found that both regions associate with POPC lipid bilayers but adopt different structures when doing so: GRK5 residues 2–31 (GRK5_2–31) was in random coil whereas GRK5_546–565 was partially helical. When the subphase for the GRK5_2–31 peptide was changed to 40% TFE/60% 10 mM phosphate pH 7.4 buffer, a large change in the SFG amide I signal indicated that GRK5_2–31 became partially helical. By inspecting the membrane behavior of two different segments of GRK5_2–31, namely, GRK5_2–24 and GRK5_25–31, we found that residues 25–31 are responsible for membrane binding, whereas the helical character is imparted by residues 2–24. With SFG, we deduced that the orientation angle of the helical segment of GRK5_2–31 is 46 ± 1° relative to the surface normal in 40% TFE/60% 10 mM phosphate pH = 7.4 buffer but increases to 78 ± 11° with higher ionic strength. We also investigated the effect of PIP₂ in the model membrane and concluded that the POPC:PIP₂ (9:1) lipid bilayer did not change the behavior of either peptide compared to a pure POPC lipid bilayer. With ATR-FTIR, we also found that Ca²⁺·calmodulin is able to extract both peptides from the POPC lipid bilayer, consistent with the role of this protein in disrupting GRK5 interactions with the plasma membrane in cells