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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Bases estructurales para la regulación alostérica de las GPCR por iones de sodio
Wei Liu1, Eugene Chun, Aaron A Thompson
1Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|July 17, 2012
Resumen
Las estructuras de alta resolución de los receptores acoplados a proteínas G (GPCR) revelan las funciones clave del agua, los iones de sodio y los lípidos en la función del receptor. Este estudio detalla la estructura estabilizada del receptor de adenosina A2A, ofreciendo nuevos conocimientos sobre la modulación del GPCR.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología Estructural
- Farmacología Farmacología.
Sus antecedentes:
- Los receptores acoplados a la proteína G (GPCR) son objetivos farmacológicos cruciales, pero sus estudios estructurales a menudo están limitados por la resolución media.
- Los moduladores alostéricos ajustan con precisión las respuestas farmacológicas GPCR, lo que requiere una comprensión estructural detallada.
Objetivo del estudio:
- Para determinar la estructura de alta resolución del receptor humano de adenosina A2A.
- Investigar el papel de las moléculas internas de agua, iones y lípidos en la estructura y función de la GPCR.
Principales métodos:
- Reingeniería del receptor humano de adenosina A2A mediante la sustitución de su tercer bucle intracelular por el apocitocromo b (((562) RIL.
- Resolución de la estructura del receptor a una resolución de 1,8 angstroms utilizando cristalografía de rayos X.
Principales resultados:
- Identificación de 57 moléculas de agua ordenadas que forman tres grupos dentro del receptor.
- Localización de un presunto ión sodio unido a Asp ((2.50) y estabilización de la hélice VI por dos colesterol.
- Observación de una intercalación de lípidos dentro de la bolsa de unión de ligandos.
Conclusiones:
- Los detalles estructurales de alta resolución aclaran las funciones potenciales del agua estructurada, los iones de sodio y los lípidos/colesterol en la estabilización de la GPCR.
- Estos hallazgos proporcionan una base para la comprensión de la modulación alostérica y el desarrollo de nuevas terapias dirigidas a los GPCR.
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01:09GPCRs Regulate Adenylyl Cylase Activity
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01:16Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
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01:08Allosteric Regulation
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
01:08Allosteric Regulation
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
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.
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