Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
Laura M Wingler1,2, Meredith A Skiba3, Conor McMahon3
1Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Science (New York, N.Y.)
|February 22, 2020
Summary
Biased agonists of G protein-coupled receptors (GPCRs) activate specific pathways. Crystal structures reveal how angiotensin II type 1 receptor (AT1R) rearrangements dictate signaling bias toward β-arrestin or Gq protein.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Biased agonists of G protein-coupled receptors (GPCRs) selectively activate downstream signaling pathways.
- Understanding receptor-ligand interactions is crucial for developing targeted therapeutics.
Purpose of the Study:
- To elucidate the structural basis of biased agonism at the angiotensin II type 1 receptor (AT1R).
- To compare the structural effects of a balanced agonist (Angiotensin II) versus biased analogs.
Main Methods:
- X-ray crystallography to determine the structures of AT1R bound to three different ligands.
- Analysis of ligand-induced conformational changes within the receptor.
Main Results:
- Crystal structures of AT1R were obtained at 2.7–2.9 angstroms with Angiotensin II and two β-arrestin-biased analogs.
- Angiotensin II induced significant rearrangements in the ligand-binding pocket and a core polar network, distinct from biased ligands.
- This polar network, containing a sodium-binding site, acts as a switch influencing signaling bias.
Conclusions:
- Structural differences explain the divergent signaling profiles of AT1R ligands.
- The identified polar network is a key determinant of biased signaling, potentially predisposing AT1R and other GPCRs to specific signaling outcomes.
More Related Videos
07:41A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
9.3K
09:19Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization
Published on: March 16, 2020
7.4K
Related Concept Videos
01:30Transducer Mechanism: G Protein–Coupled Receptors
3.6K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
3.6K
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
2.2K
Angiotensin-converting enzyme (ACE), a vital component of the renin-angiotensin-aldosterone system, is abundant in lung endothelial cells. ACE converts the inactive decapeptide, angiotensin I, into the active octapeptide, angiotensin II. This potent vasoconstrictor narrows blood vessels, increasing resistance to blood flow and elevating blood pressure. Angiotensin II also stimulates aldosterone production, encouraging kidney cells to reabsorb more sodium and water from urine, thereby increasing...
2.2K
01:09GPCRs Regulate Adenylyl Cylase Activity
7.0K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.0K
01:22Activation and Inactivation of G Proteins
10.5K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
10.5K
01:30Antihypertensive Drugs: Angiotensin II Receptor Blockers
2.2K
In the renin-angiotensin-aldosterone system, a hormone called angiotensin II plays a crucial role. It binds to the AT1 receptors in vascular smooth muscles coupled with Gq proteins. The activation of these receptors activates an enzyme called phospholipase C, which releases two molecules: inositol trisphosphate and diacylglycerol. These molecules cause a chain reaction that leads to the phosphorylation of myosin light chains and promotes interaction between actin and myosin, leading to smooth...
2.2K
01:15G Protein-coupled Receptors
16.1K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
16.1K