Sandbox Reserved 427
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<scene name='48/483884/K_or_ligand_biding_pocket_asp/1'>(Binding Site)</scene> | <scene name='48/483884/K_or_ligand_biding_pocket_asp/1'>(Binding Site)</scene> | ||
| - | 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. | + | 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''' | '''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]. | + | 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.] | [See Reference 6 for list of ligands.] | ||
'''Agonists Salvinorin A - Mechanisms, Structure, and Effects''' | '''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''' | '''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] | + | 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''' | '''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]. | + | 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== | ==Additional Features== | ||
Revision as of 08:44, 3 April 2015
Ásliding right into the DMs
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Kappa-Opioid Receptor
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