Development and validation of opioid ligand–receptor interaction models: The structural basis of mu vs. delta selectivity

Abstract

Opioid receptor binding conformations for two structurally related, conformationally constrained tetrapeptides, JOM-6 ( micro receptor selective) and JOM-13 (delta receptor selective), were deduced using conformational analysis of these ligands and analogs with additional conformational restrictions. Docking of these ligands in their binding conformations to opioid receptor structural models, based upon the published rhodopsin X-ray structure, implicates specific structural features of the micro and delta receptor ligand binding sites as forming the basis for the micro selectivity of JOM-6 and the delta selectivity of JOM-13. In particular, the presence of E229 in the micro receptor (in place of the corresponding D210 of the delta receptor) causes an adverse electrostatic interaction with C-terminal carboxylate-containing ligands, resulting in the observed preference of ligands with an uncharged C-terminus for the micro receptor. In addition, the requirement that the Phe3 side chain of JOM-13 assume a gauche orientation for optimal delta binding, whereas the Phe3 side chain of JOM-6 must be in a trans orientation for high-affinity micro binding can be largely attributed to the steric effect of replacement of L300 of the delta receptor by W318 of the micro receptor. Testing this hypothesis by examining the binding of JOM-6 and several of its key analogs with specific micro receptor mutants is described. Our initial results are consistent with the proposed ligand-receptor interaction models.

Ubiquitination Regulates Proteolytic Processing of G Protein-coupled Receptors after Their Sorting to Lysosomes

“…This intramembrane binding site is also essential for association of physiologically relevant opioid peptides with receptors, although high affinity binding of opioid peptides also requires residues present in extracellular loops (41). Thus, diprenorphine binding represents an independent measure of receptor proteolysis, which is sensitive to the integrity of the receptor's hydrophobic core.…”

Homology modeling of opioid receptor-ligand complexes using experimental constraints

“…26 Subsequent modifi cations of the parent tetrapeptides were directed toward elucidation of structural requirements for Tyr1 and Phe3 residues, which are key residues for recognition of cyclic tetrapeptides by ORs. [25][26][27][28][29][30][31][32][33] The following …”

“…[25][26][27][28][29][30][31][32][33] In particular, the cyclic tetrapeptides JOM13 (Tyr-c[D-CysPhe-D-Pen]OH, cyclized through a disulfi de bond) and JOM6 (Tyr-c[D-Cys-Phe-D-Pen]NH2, cyclized via an ethylene dithioether), are highly potent and selective for DOR and MOR, respectively. 25 The design of k -selective tetrapeptides based upon the same type scaffold as JOM13 and JOM6 has E436 been more challenging. Although cyclic tetrapeptides with high k -selectivity have not been obtained, the cyclic tetrapeptide, MP16 (Tyr-c[D-Cys-Phe-D-Cys]NH2, cyclized via a disulfi de) demonstrates nanomolar affi nity to KOR.…”

“…During the past few years we have developed a large number of cyclic tetrapeptides with high affi nity toward MOR, DOR, and KOR. [25][26][27][28][29][30][31][32][33] In particular, the cyclic tetrapeptides JOM13 ( Subsequent modifi cations of the parent tetrapeptides were directed toward elucidation of structural requirements for Tyr1 and Phe3 residues, which are key residues for recognition of cyclic tetrapeptides by ORs. [25][26][27][28][29][30][31][32][33] The following …”

Structural and Biological Exploration of Phe3–Phe4-Modified Endomorphin-2 Peptidomimetics

“…27 Since it can be supposed that the reported structure was referred to an inactive form of the receptor, we rather decided to use an active form of the MOR model as described by Mosberg. 28 The ligands were docked in to the MOR model flexibly with the Molegro Virtual Docker software (Figure 3). …”