Protein Engineering, Vol 11, 1163-1179, Copyright © 1998 by Oxford University Press
CM Topham, L Mouledous, G Poda, B Maigret and JC Meunier
The opioid receptor like (ORL1) receptor is a G-protein coupled receptor
superfamily, and regulates a plethora of neurophysiological functions. The
structural requirements for receptor activation by its endogenous agonist,
nociceptin (FGGFTGARKSARKLANQ), differ markedly from those of the
kappa-opioid receptor and its putative peptide agonist, dynorphin A
(YGGFLRRIRPKLKWDNQ). In order to probe the functional architecture of the
ORL1 receptor, a molecular model of the receptor has been built, including
the TM domain and the extra- and intracellular loops. An extended binding
site able to accommodate nociceptin-(1-13), the shortest fully active
analogue of nociceptin, has been characterized. The N-terminal FGGF
tetrapeptide is proposed to bind in a highly conserved region, comprising
two distinct hydrophobic pockets in a cavity formed by TM helices 3, 5, 6
and 7, capped by the acidic second extracellular (EL2) loop controlling
access to the TM elements of the peptide binding site. The nociceptin
conformation provides for the selective preference of the ORL1 receptor for
nociceptin over dynorphin A, conferred by residue positions 5 and 6 (TG
versus LR), and the favourable interaction of its highly positively charged
core (residues 8-13) with the EL2 loop, thought to mediate receptor
activation. The functional roles of the EL2 loop and the conserved
N-terminal tetrapeptide opioid 'message' binding site are discussed in the
context of the different structural requirements of the ORL1 and
kappa-opioid receptors for activation.
ARTICLES
Molecular modelling of the ORL1 receptor and its complex with nociceptin
Unite de Neuropharmacologie Moleculaire, Institut de Pharmacologie et de Biologie Structurale, CNRS UPR 9062, Toulouse, France.
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