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Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
Published on: March 10, 2020
Solution- and solid-state NMR studies of GPCRs and their ligands
Satita Tapaneeyakorn1, Alan D Goddard, Joanne Oates
1Biomembrane Structure Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Biochimica Et Biophysica Acta
|October 19, 2010
Summary
Nuclear Magnetic Resonance (NMR) spectroscopy offers valuable insights into G protein-coupled receptor (GPCR) and ligand interactions, crucial for drug discovery when crystallization is challenging. This review guides new researchers in utilizing NMR for studying these vital protein-ligand interactions.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- G protein-coupled receptors (GPCRs) are critical membrane proteins involved in numerous cellular signaling pathways and are major drug targets.
- Structure-based drug design is a promising approach for novel drug discovery, but GPCR crystallization for X-ray studies is difficult.
- Nuclear Magnetic Resonance (NMR) spectroscopy provides an alternative method to study GPCRs and their interactions.
Purpose of the Study:
- To introduce new investigators to the application of NMR spectroscopy for studying GPCR/ligand interactions.
- To provide guidelines for selecting suitable GPCR and ligand systems for NMR studies, including efficient isotope labeling strategies.
- To offer an overview of sample environments that facilitate high-resolution structural information from NMR spectra.
Main Methods:
- Solution- and solid-state NMR spectroscopy techniques.
- Isotope labeling strategies for GPCRs and ligands.
- Analysis of protein-ligand interactions using NMR data.
Main Results:
- NMR approaches have yielded significant insights into GPCR-ligand interactions, complementing traditional structural biology methods.
- The review outlines practical considerations for implementing NMR studies on GPCR systems.
- Guidelines are provided for optimizing sample conditions to obtain high-resolution structural data.
Conclusions:
- NMR spectroscopy is a powerful tool for investigating GPCR-ligand interactions, essential for structure-based drug discovery.
- This review serves as a foundational resource for researchers new to GPCR NMR studies.
- The presented guidelines aim to enhance the efficiency and success of NMR-based GPCR research.
Related Concept Videos
01:15G Protein-coupled Receptors
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...
01:15G Protein-coupled Receptors
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...
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01:30Transducer Mechanism: G Protein–Coupled Receptors
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, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
01:21G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
01:21G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.