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Heterotrimeric G proteins have a crucial role as molecular switches in signal transduction pathways mediated by G-protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP-GDP exchange on the G protein alpha-subunit. The complex series of interactions and conformational changes that connect agonist binding to G(More)
The structure of a heterotrimeric G protein reveals the mechanism of the nucleotide-dependent engagement of the alpha and beta gamma subunits that regulates their interaction with receptor and effector molecules. The interaction involves two distinct interfaces and dramatically alters the conformation of the alpha but not of the beta gamma subunits. The(More)
Many signalling cascades use seven-helical transmembrane receptors coupled to heterotrimeric G proteins (G alpha beta gamma) to convert extracellular signals into intracellular responses. Upon nucleotide exchange catalysed by activated receptors, heterotrimers dissociate into GTP-bound G alpha subunits and G beta gamma dimers, either of which can modulate(More)
In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane(More)
Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors.(More)
Aluminium fluoride (AIF-4) activates members of the heterotrimeric G-protein (G alpha beta gamma) family by binding to inactive G alpha.GDP near the site occupied by the gamma-phosphate in G alpha.GTP (ref. 3). Here we describe the crystal structure of transducin alpha.GDP activated with aluminium fluoride (Gt alpha.GDP.AIF-4.H2O) at 1.7 A, a resolution(More)
In multicellular organisms from Caenorhabditis elegans to Homo sapiens, the maintenance of homeostasis is dependent on the continual flow and processing of information through a complex network of cells. Moreover, in order for the organism to respond to an ever-changing environment, intercellular signals must be transduced, amplified, and ultimately(More)
The interaction between receptors and guanine nucleotide binding (G) proteins leads to G protein activation and subsequent regulation of effector enzymes. The molecular basis of receptor-G protein interaction has been examined by using the ability of the G protein from rods (transducin) to cause a conformational change in rhodopsin as an assay. Synthetic(More)
Heterotrimeric guanine-nucleotide-binding proteins (G proteins) act as molecular switches in signaling pathways by coupling the activation of heptahelical receptors at the cell surface to intracellular responses. In the resting state, the G-protein alpha subunit (Galpha) binds GDP and Gbetagamma. Receptors activate G proteins by catalyzing GTP for GDP(More)