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Introduction

This scene is of the within the Kappa Opioid Receptor by Group 3.

-"Kappa-Opioid receptors mediate the regulation of pain, respiratory drive, mood"
-"structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR"
-consequences of stress as well as depression/anxiety
-hallucinogenic effects
-talk about mu and kappa OR
-intro to kappa-OR subtype selectivity

Overall Structure

Copy and paste the following line where you want the scene link to appear (scroll down if needed) and edit the TextToBeDisplayed:

-describe the overall size of the molecule: how massive it is, how many alpha helices and beta sheets it contains.

-describe the two different dimmers that form the protien and how and along which alpha helices the dimmers coordinate with each other

-describe how the protein fits in the cell membrane, how much is contained in the membrane.

-describe which parts are conserved and which parts make it a unique molecule like how the sulfide bond near the n-terminus among other feature distinguishes itself from CXCR4

-describe the structure and shape of the binding pocket, discuss how these structural conformations make it unique.

Binding Interactions

Active Site of kappa Opioid Receptors

The human kappa opioid receptor (hKOR) ligand binding pocket displays a unique combination of key characteristics both shared with and distinct from those in the chemokine and aminergic receptor families [2].

Common Ligands of Opioid Receptors

The majority of endogenous opioid peptides have a defined preference to specific subtypes, for example, endorphins act via DORs and MORs, whereas dynorphins preferentially activate KORs. Several KOR selective partial agonists and antagonists have been developed as potential antidepressants, anxiolytics, and anti-addiction medications, whereas a widely abused, naturally occurring hallucinogen Salvinorin A (SalA) was also found to be a highly selective KOR agonist [2] [5].

[See Reference 6 for list of ligands.]

Agonists Salvinorin A - Mechanisms, Structure, and Effects

Salvinorin A (SalA), a naturally occurring diterpene from the widely abused hallucinogenic plant Salvia divinorum represents an exceedingly potent and selective KOR agonist. It has been found that the 2-acetoxy moiety on SalA interacts with Cys315

The elucidation of a large binding cavity with a multitude of potential anchoring points begins to explain both the extreme structural diversity of hKOR drugs and differences in their receptor interaction modes, as supported by differential effects of various site-directed mutations on the binding properties of chemically diverse ligands [2] [7].

[See reference 7 for more information.]

Antagonists JDTic - Mechanisms, Structure, and Effects

JDTic, has exceptionally high affinity (Ki = 0.32 nM), potency, long duration of action and amore than 1000 fold selectivity for hKOR as compared to other Opioid receptor (OR) subtypes. The protonated amines in both piperidine and isoquinoline moieties of the ligand form salt bridges to the Asp 138 3.32 side chain. The piperidine amine is essential for binding. The isoquinoline nitrogen can be replaced by carbon, oxygen or sulfur atoms with only ~10 to 50 fold reduction in affinity. A “V” shaped conformation was found in the crystal structure of JDTic by itself and which showed its amino groups coordinating a water molecule. The anchoring-type interaction of two amino groups with Asp138 likely fixes the ligand in this characteristic V-shape. The distal hydroxyl groups on both the piperidine and isoquinoline moieties of JDTic when removed result in a 100 fold reduction of affinity. JDTic interacts with four residues of the binding pocket that differ in other closely related ORs, which are thought to contribute to the subtype selectivity of JDTic and other KOR-selective ligands [2] [4].

Val 108, Val 118, Ile 294 and Tyr 312

The isopropyl group from JDTic reaches deep in the orthosteric pocket to form a hydrophobic interaction with a conserved Trp 287 side chain, possibly playing a critical role in the pharmacological properties of this ligand. Analysis of the ligand-receptor interactions has revealed important molecular details responsible for the exceptionally high affinity and subtype selectivity of JDTic-a small molecule antagonist with a broad therapeutic potential [2] [5].

[See reference 2 for more information.]

Additional Features

The k-opioid receptor is a protein, with inter-membrane alpha helices displayed in red.

A hydropathy plot for this receptor reinforces this fact, with a large span of the molecule shown again as trans-membrane alpha helices.

Based on the Ramachandran plot for the general case showing the standard phi and psi angle, it can be inferred that the majority of the secondary structure is composed , with the alpha helices shown in purple and the beta sheets shown in yellow.

The large cluster of dots shown close to the origin of the plot corresponds to small angles that imply an alpha helix.

Quiz Question 1

Why might the , highlighted in blue, be located here in the protein? (Explain how its location and other properties of the protein maintain binding specificity.) What basic conformational changes may the protein undergo while binding to ligands?

Quiz Question 2

What properties and functional groups would a substrate binding to the active site of the Kappa-opioid receptor probably possess? Explain your reasoning.

See Also

• UvrABC
• Opioid Receptor
• Mu Opioid Receptor Bound to a Morphinan Antagonist
• G protein-coupled Receptor

Credits

Introduction - Patrick Harney

Overall Structure - Matthew Long

Drug Binding Site - Brandon Kittredge

Additional Features - Jacob Kellet

Quiz Question 1 - Leah Caffrey

Quiz Question 2 - Bridget Kilkenny

References

1. Chavkin C., The Therapeutic Potential of κ-Opioids for Treatment of Pain and Addiction. Neuropsychopharmacology. 2011;36:369–370.

2. Wu H., Wacker D., Mileni M., Structure of the human kappa opioid receptor in complex with JDTic. Nature. 2012;485:327-332. PMID:22437504

3. Martinez-Mayorga K., Byler K., Yongye A., et al. Ligand/kappa-opioid Receptor Ineractions: Insights from the X-Ray Crystal Structure. Eur J. Med. Chem. 2013; 66: 114-121.

4. Leonis, Georgios, Aggelos Avramopoulos, Ramin Ekhteiari Salmas, Serdar Durdagi, Mine Yurtsever, and Manthos G. Papadopoulos. "Elucidation of Conformational States, Dynamics, and Mechanism of Binding in Human κ‐Opioid Receptor Complexes." Journal of Chemical Information and Modeling (n.d.): n. pag. ACS. Web.

5. Aldrich, Jane V., and Jay P. Mclaughlin. "Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development." The AAPS Journal 11.2 (2009): 312-22. Web.

6.Henriksen, G., and F. Willoch. "Imaging of Opioid Receptors in the Central Nervous System." Brain 131.5 (2007): 1171-196. Web.

7.Roth, B. L. "Salvinorin A: A Potent Naturally Occurring Nonnitrogenous Kappa Opioid Selective Agonist." Proceedings of the National Academy of Sciences 99.18 (2002): 11934-1939. Web.