The analgesic domain of interferon-alpha2b contains an essential proline(39) residue.
OBJECTIVE
It has been demonstrated that there are structural and functional similarities between interferon-alpha (INF-alpha) and endorphins. We have reported that there are distinct domains in the IFN-alpha molecule that mediate immune and analgesic effects, respectively, and that the opioid-like analgesic effect of IFN-alpha is mediated by the mu opioid receptor, thus inferring that the analgesic domain of IFN-alpha consists of Tyr(122) and the residues around Tyr(122) in the tertiary structure. The aim of this work was to further explore the molecular basis for the analgesic domain of IFN-alpha.


METHODS
By using site-directed mutagenesis, the structure of IFN-alpha was changed and a mutant of IFN-alpha was obtained. Then, the antiviral activity and opioid-like analgesic activity of IFN-alpha were measured.


RESULTS
When the Pro(39) residue of IFN-alpha, which is located close to the Tyr(122) residue in the tertiary structure, was mutated to Gly, the analgesic activity of this mutant was lost completely, but the antiviral activity of IFN-alpha was maintained compared with wild-type IFN-alpha.


CONCLUSIONS
Combining the sequence of the endomorphin, it is suggested that the Pro(39) residue is one of the constituents of the analgesic domain of IFN-alpha and contributes to IFN-alpha binding to the mu opioid receptor.
Department of Neurobiology, Second Military Medical University, Shanghai, PR China.
Yun-Xia
YX
Wang
Li-Hua
LH
Song
Yi-Zhang
YZ
Chen
Chun-Lei
CL
Jiang
D000700:Analgesics / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry* / Q000276:immunology; D008297:Male; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed / Q000235:genetics / Q000276:immunology; D010146:Pain / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D011392:Proline / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins
D000700:Analgesics; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D011392:Proline; D005998:Glycine