A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist

The FEBS Journal
Brian E KaneDavid M Ferguson

Abstract

Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. Th...Continue Reading

References

Feb 26, 1985·European Journal of Pharmacology·R A LahtiP F Von Voigtlander
Aug 1, 1987·Molecular and Cellular Biology·C Chen, H Okayama
May 1, 1983·Journal of Ethnopharmacology·L J ValdésA G Paul
Jun 1, 1994·Journal of Ethnopharmacology·D J Siebert
Aug 16, 1994·Proceedings of the National Academy of Sciences of the United States of America·H KongT Reisine
Jul 1, 1996·Protein Engineering·I Alkorta, G H Loew
Feb 21, 1998·Proceedings of the National Academy of Sciences of the United States of America·P CowardB R Conklin
Jul 14, 2000·Journal of Medicinal Chemistry·W C StevensP S Portoghese
Apr 25, 2002·Journal of the American Chemical Society·Yirong MoDavid M Ferguson
Aug 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·Bryan L RothRichard B Rothman
Jan 9, 2003·Progress in Medicinal Chemistry·Iain McFadyenDavid M Ferguson
May 5, 2005·Bioorganic & Medicinal Chemistry Letters·Cécile BéguinBruce M Cohen
Jul 22, 2005·Journal of Medicinal Chemistry·Wayne W HardingThomas E Prisinzano
Jan 26, 2006·Pharmacology, Biochemistry, and Behavior·Christopher R McCurdyMarcelo J Nieto

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Citations

May 15, 2008·Chemical Reviews·Thomas E Prisinzano, Richard B Rothman
Apr 3, 2008·Journal of Medicinal Chemistry·Kevin TidgewellThomas E Prisinzano
Aug 27, 2009·Organic & Biomolecular Chemistry·Denise S SimpsonThomas E Prisinzano
Mar 30, 2011·Pharmacological Reviews·Christopher W CunninghamThomas E Prisinzano
Jul 26, 2014·Journal of Chemical Information and Modeling·Georgios LeonisManthos G Papadopoulos
Jan 20, 2010·Journal of Molecular Graphics & Modelling·Donna L McGovernRichard B Westkaemper
May 6, 2008·Journal of Molecular Graphics & Modelling·Nidhi SinghChristopher R McCurdy
Oct 24, 2007·Peptides·Richard J Bodnar
Apr 10, 2008·The FEBS Journal·Luca GentilucciAndrea Bedini
Jun 14, 2019·Journal of Psychopharmacology·Adam W KeaslingJames O Fajemiroye
Aug 19, 2020·Natural Product Reports·Sarah J HillRyan A Shenvi
Oct 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bronwyn M KivellThomas E Prisinzano
Apr 2, 2017·Journal of Computer-aided Molecular Design·A F Marmolejo-Valencia, K Martínez-Mayorga
Apr 1, 2018·Progress in Neuro-psychopharmacology & Biological Psychiatry·Konstantin A DeminAllan V Kalueff
Sep 15, 2017·Organic Letters·Alexander M SherwoodThomas E Prisinzano
Feb 26, 2008·Journal of Medicinal Chemistry·Brian E KaneDavid M Ferguson

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