May 31, 2012
RESEARCHERS DISCOVER STRUCTURE OF OPIOID RECEPTORS
Opioid receptors are proteins found on the surface of cells in the nervous and digestive systems that bind opioid proteins, molecules that naturally occur in the body and play a role in regulating pain, pleasure, mood, addiction, and digestion. An array of legal and illegal drugs such as morphine, codeine, and heroin also bind to these receptors and control their activity, but usually with unwanted side effects such as hallucinations and addiction, which limits their clinical use. The development of selective therapeutics that control the activity of opioid receptors without these side effects holds great promise as pain relievers, anti-depressants, and anti-anxiety treatments. The development of such agents could have a revolutionizing effect on the treatment of acute and chronic pain, several neuropsychiatric disorders, and addiction.
Dr. Raymond Stevens, partly funded by the NIH Common Fund’s Structural Biology program and the National Institute of General Medical Science’s Protein Structure Initiative, along with colleagues, has published the three-dimensional structures of two members of the human opioid receptor family- the kappa opioid receptor (KOR) and the nociceptin/orphanin FQ peptide receptor (NOP). As reported in the May 17, 2012 issue of Nature, these structures reveal unprecedented detail about the shape of these receptors, which may allow researchers to design drugs that can interact with these receptors in specific ways to elicit only the desired effects. KOR is the only receptor that binds the active ingredient in the plant Salvia divinorum (also known as “Salvia” or “Magic Mint”), which has recently gained popularity as a recreational drug of abuse causing hallucinations and psychedelic experiences (see the National Institute of Drug Abuse InfoFacts: Salvia). The part of the receptors where drugs and other molecules bind, called the binding pocket, is very large in both KOR and NOP. KOR and NOP differ in only a few specific places within the binding pocket, but these differences result in significant changes in the shape of the pocket, explaining why some molecules specifically bind to one receptor, but not the other. In the same issue of Nature, Dr. Brian Kobilka and colleagues published the structures of the mu and delta opioid receptors; collectively, these four papers reveal the structures of the entire family of human opioid receptors. Drs. Stevens and Kobilka used sophisticated techniques, developed in part through previous Common Fund support, to create the protein crystals needed to reveal the underlying protein structure. These studies provide a major clue in understanding the selectivity of opioid receptors, opening up new avenues of research into basic research about brain function and consciousness, as well as the development of clinically useful therapeutics.
Wu H, Wacker D, Katritch V, Mileni M, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Structure of the human kappa opioid receptor in complex with JDTic. Nature, 2012 Mar 21 (online publication date); 485(7398): 327-32. PMID: 22437504.
Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang X-P, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature, 2012 May 16; 485(7398):395-9. PMID: 22596163.
Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature, 2012 Mar 21 (online publication date); 485(7398): 321-6. PMID: 22437502.
Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka B. Structure of the delta-opioid receptor bound to naltrindole. Nature, 2012 May 16; 485(7398): 400-4. PMID: 22596164.