Shim, Joong-Youn; Rudd, James; Ding, Tomas T.
Distinct second extracellular loop structures of the brain cannabinoid CB1 receptor: Implication in ligand binding and receptor function
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 79:581-597, FEB 2011

The G-protein-coupled receptor (GPCR) second extracellular loop (E2) is known to play an important role in receptor structure and function. The brain cannabinoid (CB1) receptor is unique in that it lacks the interloop E2 disulfide linkage to the transmembrane (TM) helical bundle, a characteristic of many GPCRs. Recent mutation studies of the CB1 receptor, however, suggest the presence of an alternative intraloop disulfide bond between two E2 Cys residues. Considering the oxidation state of these Cys residues, we determine the molecular structures of the 17-residue E2 in the dithiol form (E2(dithiol)) and in the disulfide form (E2(disulfide)) of the CB1 receptor in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer, using a combination of simulated annealing and molecular dynamics simulation approaches. We characterize the CB1 receptor models with these two E2 forms, CB1 (E2(dithiol)) and CB1(E2(disulfide)), by analyzing interaction energy, contact number, core crevice, and cross correlation. The results show that the distinct E2 structures interact differently with the TM helical bundle and uniquely modify the TM helical topology, suggesting that E2 of the CBI receptor plays a critical role in stabilizing receptor structure, regulating ligand binding, and ultimately modulating receptor activation. Further studies on the role of E2 of the CB1 receptor are warranted, particularly comparisons of the ligand-bound form with the present ligand-free form. Proteins 2011; 79:581-597. (C) 2010 Wiley-Liss, Inc.

DOI:10.1002/prot.22907

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