Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. Chem Biol 2015 Jun 18;22(6):764-75
Date
06/20/2015Pubmed ID
26091169Pubmed Central ID
PMC4507497DOI
10.1016/j.chembiol.2015.05.012Scopus ID
2-s2.0-84934953131 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides.
Author List
Vardy E, Sassano MF, Rennekamp AJ, Kroeze WK, Mosier PD, Westkaemper RB, Stevens CW, Katritch V, Stevens RC, Peterson RT, Roth BLAuthor
Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAmphibians
Analgesics, Opioid
Animals
Behavior, Animal
Binding Sites
Humans
Kinetics
Molecular Dynamics Simulation
Molecular Sequence Data
Oligopeptides
Opioid Peptides
Peptides
Protein Structure, Tertiary
Receptors, Opioid
Sequence Alignment
Skin
Species Specificity
Zebrafish
