Structural insights into G protein-coupled receptor activation and signaling
Abstract/Contents
- Abstract
- G protein coupled receptors (GPCRs) are a class of cell-surface receptors that mediate complex cellular responses to a myriad of physiological stimuli, from photons and neurotransmitters, to hormones, peptides, and even full proteins. GPCR signaling underlies almost all of physiology; this central importance to human health and disease is reflected in the fact that approximately 30% of all FDA approved drugs target GPCRs. Ligand action at GPCRs mediates intracellular signaling through heterotrimeric G proteins, as well as G protein-independent pathways. Over the past decade, a structural framework has allowed for a more precise understanding of ligand-mediated activation in rhodopsin-like GPCRs, as well as the molecular mechanism for GPCR signaling through the stimulatory G protein, Gs. My work expands this structural understanding of GPCR activation and signaling by exploring two novel signaling systems in the GPCR family for which structural information is lacking. First, I describe work on the structure of a peptide-activated mu-opioid receptor (muOR) in complex with the inhibitory G protein, Gi. As signaling through Gi is responsible for the beneficial aspects of opioids, the structure of this complex can help guide the design and discovery of novel therapeutics with reduced liabilities. I then show the structural mechanism of activation in a family C GPCR, the metabotropic glutamate receptor 5 (mGlu5). Family C receptors are unusual in that, as well as the GPCR-defining 7-transmembrane (7TM) domain, they possess relatively large amino-terminal extracellular domains (ECDs) that form obligate dimers and contain the orthosteric ligand-binding sites. Taken together, this work presents novel insights into GPCR activation and signaling.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Koehl, Antoine |
|---|---|
| Degree supervisor | Kobilka, Brian K |
| Thesis advisor | Kobilka, Brian K |
| Thesis advisor | Feng, Liang, 1976- |
| Thesis advisor | Skiniotis, Georgios |
| Degree committee member | Feng, Liang, 1976- |
| Degree committee member | Skiniotis, Georgios |
| Associated with | Stanford University, Department of Structural Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Antoine Koehl. |
|---|---|
| Note | Submitted to the Department of Structural Biology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Antoine Koehl
- License
- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
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