On the role of extracellular loops of opioid receptors in conferring ligand selectivity

FEBS Letters

Ferguson, David M.¹  Metzger, Thomas G.¹ 

[1] Department of Medicinal Chemistry and Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA

关键词: Opioid receptor;    Extracellular loops;    Chimeric receptor;    Ligand binding;    DAMGO;   

DOI  :  10.1016/0014-5793(95)01185-H

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Based on an analysis of results taken from site-directed mutagenesis studies performed on opioid receptors, a role for the extracellular loops in conferring opioid subtype selectivity is proposed. It is suggested that the extracellular loop regions (which represent the region of highest sequence variability among opioid subtypes) interact with opioid ligands in a primarily non-specific fashion. Although these interactions are non-specific, they appear to play a discriminatory role in ligand binding and, in certain cases, prevent particular ligands from binding among receptor subtypes. We propose that selectivity may be imparted through a mechanism of exclusion, rather than specific pharmacophore recognition within the extracellular loops and N-terminal domain. This hypothesis is supported by a careful analysis of the binding profiles of several selective and non-selective ligands to a variety of chimeric mutants. These results, when combined with results taken from single-point mutation experiments point to the existence of a high affinity binding pocket within the transmembrane region which may be common among the opioid subtypes.

【 授权许可】

Unknown