Comparative molecular modeling on 3D-structure of opioid receptor-like 1 receptor

To build the three-dimensional structure of opioid receptor-like 1 (ORL1) receptor.

Structural elements of ORL1 receptor were predicted from sequence alignments of opioid and related receptors of G protein-coupled receptor (GPCR) based on (i) the consensus, biophysical interpretations of alignment-derived properties, and (ii) tertiary structural homology to frog rhodopsin; The extracellular loops of ORL1 were built by self-constructed database searching based on geometrical constraints; initial model was refined computationally with energy minimization by molecular mechanics method.

The calculated structure of ORL1 receptor has clusters of hydrogen bonds existing in interhelices and extracellular loops; the ORL1 receptor has a possible ligand-binding "crevice" situated on the extraside of the transmembrane domains between helices 3, 5, 6, and 7, which is partially covered by the extracellular loop 2 (EL-2); The binding cavity may consist of a "highly conserved region" involving the residues of Asp130, Tyr131, and an outer "conservatively variable region" containing the residues near the interface of transmembrane (TM) helices-EL loops; The molecular model obtained is qualitatively consistent with ligand affinities, hybrid peptide studies, and other experimental data.

The structural model of ORL1 receptor from this study is helpful for clarifying experimental observations of ligands interacting with opioid receptors, and for designing new biological investigations.