Identification of Active-State Kappa-Opioid Receptor Crystal Structure May Facilitate the Design of Improved Analgesics

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κ-opioid receptors mediate analgesia and their activation was shown to also produce dysphoria, hallucinations, and malaise.
κ-opioid receptors mediate analgesia and their activation was shown to also produce dysphoria, hallucinations, and malaise.

Elucidation of the crystal structure of κ-opioid receptors (KORs) in their active state may facilitate the design of optimized analgesics, devoid of psychoactive effects and of addictive properties.1 Results of this multi-institutional study led by scientists at the University of North Carolina, Chapel Hill, were published in Cell.

KORs mediate analgesia and KOR agonists were shown to also produce dysphoria, hallucinations, and malaise — unlike δ- and μ-opioid receptor (MOR) agonists, which are associated with positive reinforcement.2-4 KORs are expressed in brain regions that are part of the stress axis, including the paraventricular hypothalamus and claustrum, and colocalize with MORs in most regions.2

“Biased agonism” refers to the selective activation of “beneficial,” but not of “deleterious” signaling pathways downstream of G protein-coupled receptors such as KORs, that can be leveraged for the development of biased ligands with optimized therapeutic benefits.5 A biased agonist for KORs favoring downstream activation of G protein signaling over β-arrestin recruitment (responsible for reductions in extracellular dopamine) was found to have dose-dependent antinociceptive and antipruritic properties in animal models.6 These properties were not accompanied with dysphoric or sedative effects and levels of dopamine release were maintained.

In the Cell study, researchers sought to determine the crystal structure of KOR in its active state to identify key determinants for the receptor's selectivity and signaling bias.1 The investigators used nanobodies — small single-domain camelid-derived heavy chain-only antibodies — which have the ability, when bound to their target, to “stabilize specific protein conformation and thus serve as chaperones in crystallography.”7 Nanobodies were raised by injecting a llama with KOR liposomes bound to salvinorin A, a selective KOR agonist, and one of the produced nanobodies, found to stabilize KOR in an active-state conformation when paired with an epoxymorphinan ligand, was selected.3,7 

Comparison of KOR in its active vs inactive state (bound to a KOR antagonist) allowed the identification of structural changes of the receptor specific to its activation status, which include rearrangements in the relative position of the receptor's transmembrane helices. In addition, mechanisms likely to underlie KOR activation were uncovered — namely, structural changes in transmembrane domain 3 residue interfaces — and structural determinants of ligands critical for both KOR-biased signaling and opioid receptor subtype selectivity were identified.

The investigators concluded that their findings, “provide molecular insights into [KOR] structure and function,” and that, “Given the urgent need to develop safer opioid medications in an effort to battle the growing opioid epidemic, these molecular insights could greatly accelerate the design of novel [KOR] ligands through structure-enabled technologies and large-scale virtual ligand screening.”1

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  1. Che T, Majumdar S, Zaidi SA, et al. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell. 2018;172(1):55-67.
  2. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44-55.
  3. Sante AB, Nobre MJ, Brandão ML. Place aversion induced by blockade of mu or activation of kappa opioid receptors in the dorsal periaqueductal gray matter. Behav Pharmacol. 2000;11(7-8):583-589.
  4. Yan F, Roth BL. Salvinorin A: a novel and highly selective k-opioid receptor agonist. Life Sci. 2004;75(22):2615-2619.
  5. Kenakin T, Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov. 2013;12(3):205-216.
  6. Brust TF, Morgenweck J, Kim SA, et al. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal. 2016;9(456):ra117.
  7. Beghein E, Gettemans J. Nanobody technology: a versatile toolkit for microscopic imaging, protein-protein interaction analysis, and protein function exploration. Front Immunol. 2017;8:771.
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