We propose to develop a deeper understanding of the structural basis for the behavior/function of the opioid receptor subfamily of G protein-coupled receptors (GPCR). Structures of all three opioid receptors: ? -opioid receptor (MOR), ? -opioid receptor (KOR), ?-opioid receptor (DOR), and the opioid-like nociceptin/orphanin FQ opioid-like receptor (NOP), have recently been solved. This breakthrough created a unique opportunity to pursue a comprehensive understanding of ligand recognition and selectivity, as well as structural mechanisms of opioid receptor activation and biased signaling. Attaining this goal will require solving a large number of structures of ligand-receptor complexes similar to what is routinely done in structure based drug design targeting soluble proteins. This is now possible since our GPCR Structure Determination Pipeline (GSDP) and our newly developed GPCR Protein Fusion Toolchest has enabled large-scale structure determination of ligand-receptor complexes. The GSDP has been used by us in the successful structure determination of 14 different human GPCRs and their complexes, including two new receptors in activated states with bound agonist. In this proposed study, we will conduct similar efforts toward the crystallization and structural determination of ligand-receptor complexes of all of the receptors in the opioid family using agonists, antagonists, inverse agonists, and allosteric modulators. Criteria for opioid receptor and signaling pathway selectivity will be approached by attempting structure determination of several complexes of functional near-wild type constructs and rationally designed mutants. Within three specific aims we will solve several ligand-receptor structures on (1) KOR, (2) NOP, and (3) MOR and DOR.

Public Health Relevance

Structure-based drug design relies on experimentally determined three-dimensional structure of target proteins of which availability for GPCR targets had been quite limited until five years ago. With rapid progress in technologies and experimental approaches, we are now able to generate a large number of structures that can then be used to design new therapeutics targeting opioid receptors that are selective and with reduced side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
1P01DA035764-01A1
Application #
8667565
Study Section
Special Emphasis Panel (ZRG1-BCMB-S (40))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$844,634
Indirect Cost
$192,425
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Robinson, J Elliott; Vardy, Eyal; DiBerto, Jeffrey F et al. (2015) Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology 40:2614-22

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