Xing, Changrui
(2020)
Structure Elucidation, Signaling Mechanism and Structure-Based Lead Design of the Human Cannabinoid Receptor 2 (CB2).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cannabinoid receptor 2 (CB2) has an important role in mediating immune signal transduction and is an attractive therapeutic target for chronic neuropain, osteoporosis, autoimmune diseases, and tumors of immune origin. Unlike CB1, which is expressed in the central nervous system (CNS), CB2 is primarily expressed in cells of the immune system and its selective modulation will not produce psychoactive effects. This feature has attracted great interest in CB2, particularly since the anti-obesity drug Rimonabant (CB1 antagonist) was withdrawn from the European market due to depression side effects.
Despite research efforts to date, the CB2 active-state structure, activation mechanism, and allosteric binding features remain elusive, representing a significant hindrance in the development of novel CB2 agonist and allosteric modulators. Thus, in this study, we first unveiled the cryo-EM structure of CB2-Gi signaling complex to gain an unprecedented understanding of the structural and functional mechanisms inherent to CB2 using high-end biophysical and biochemical approaches with purified functional CB2. Next, we developed and applied an innovative residual energy calculation algorithm to aid in the design of a pair of selective CB2 agonist and inverse agonist in order to validate our putative mechanism of receptor activation involving the structural arrangement of critical residues. Then, we investigated the binding features of selective CB2 agonists, as well as the CB2 biased ligand and CB2 positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).
Collectively, the results from this study will provide insightful information to facilitate structure-based design and discovery of high-affinity and/or high-selectivity CB2 ligands that can be developed as CB2-targeting therapeutic agents.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
3 August 2020 |
| Date Type: |
Publication |
| Defense Date: |
14 July 2020 |
| Approval Date: |
3 August 2020 |
| Submission Date: |
31 July 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
136 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
3D Structure of Cannabinoid Receptor CB2; Activation Mechanisms of CB2 and CB1; Agonist-bound CB2- Gi Signaling Complex; CB2 Agonist; CB2 Coupling Specificity for Gi; CB2 Drug Discovery; CB2 Inverse Agonist; Cryo-EM structure; Gi Coupling Versatility; Residual Energy Contribution; CB2 biased ligand; CB2 allosteric modulators |
| Date Deposited: |
03 Aug 2020 13:47 |
| Last Modified: |
03 Aug 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39496 |
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