Activation of G-protein-coupled receptors: a common molecular mechanism

Karnik, Sadashiva S.; Gogonea, Camelia; Patil, Supriya; Saad, Yasser; Takezako, Takanobu

doi:10.1016/j.tem.2003.09.007

Cited by 172 publications

(153 citation statements)

References 62 publications

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“…These changes would be required for receptor activation and transduction of ligand binding to effector activation, for example. In fact, it is accepted that activation of GPCRs results from agonist-provoked changes in the conformation of the receptor that drives the equilibrium between the inactive and active state in favor of the latter (Gether and Kobilka, 1998;Karnik et al, 2003). The ability of ligands to change the shape of the receptor [and conversely of receptors to stabilize in distinct active conformations in response to different ligands (Lu et al, 2005)] and thereby transfer the signal to domains involved in G protein activation suggests that allosteric GPCR modulators (May et al, 2007) may be potential candidates for pharmacological chaperoning.…”

Section: Relation Between the Overall Receptor Structure And The Smentioning

confidence: 99%

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

2007

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Section: Relation Between the Overall Receptor Structure And The Smentioning

confidence: 99%

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

2007

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“…Cys-109 forms a disulfide bond with Cys-188 in EC2, and disruption of the disulfide bond blocks ligand-dependent activation (13). This disulfide bond is found in over 91% of all human GPCRs and is important in many other receptors (19). Leu-112 was identified as an essential residue in TM3 (11), and a receptor with a L112A mutation failed to respond to C5a (18).…”

Section: First and Third Extracellular Loops Of C5armentioning

confidence: 99%

Genetic Analysis of the First and Third Extracellular Loops of the C5a Receptor Reveals an Essential WXFG Motif in the First Loop

Klco

Nikiforovich

Baranski

2006

Journal of Biological Chemistry

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The extracellular loops of G protein-coupled receptors (GPCRs) frequently contain binding sites for peptide ligands. However, the mechanism of receptor activation following ligand binding and the influence of the extracellular loops in other aspects of receptor function are poorly understood. Here we report a structure-function analysis of the first and third extracellular loops of the human C5a receptor, a GPCR that binds a 74-amino acid peptide ligand. Amino acid substitutions were randomly incorporated into each loop, and functional receptors were identified in yeast. The first extracellular loop contains a large number of positions that cannot tolerate amino acid substitutions, especially residues within the WXFG motif found in many rhodopsin-like GPCRs, yet disruption of these residues does not alter C5a binding affinity. These results demonstrate an unanticipated role for the first extracellular loop, and the WXFG motif in particular, in ligand-mediated activation of the C5a receptor. This motif likely serves a similar role in other GPCRs. The third extracellular loop, in contrast, contains far fewer preserved residues and appears to play a less essential role in receptor activation.G protein-coupled receptors (GPCRs) 2 are the largest class of membrane-bound receptors, with more than 850 members in the human genome (1). The majority of GPCRs is grouped in the rhodopsin family by the presence of a small number of conserved amino acids in the transmembrane (TM) bundle, such as the DRY motif at the cytoplasmic end of TM3 and the NPXXY motif in TM7 (2). These receptors share a similar molecular architecture within the seven-helix bundle, which was originally represented by the ␣-carbon template of the Baldwin model (3) and later confirmed by the high resolution structure of bovine rhodopsin (4). The extracellular loops, in contrast, are more divergent, both in length and function (5). Ligands frequently bind to the extracellular loops, and the variability of the loops is not surprising when considering the range of ligands known to interact with GPCRs. For many GPCRs, especially those that bind larger peptide ligands, the mechanisms by which ligand binding stimulates G protein activation and how the extracellular loops can influence receptor activation are poorly understood. Considering that more than half of all prescribed medications target GPCRs, mostly by disrupting or mimicking ligand binding (6), a better understanding of the function of the extracellular loops is extremely important.To elucidate how GPCRs function as molecular switches to transduce signals, we study the complement factor 5a receptor (C5aR), a rhodopsin-like GPCR expressed primarily on the surface of neutrophils and other myeloid cells. C5a, a 74-amino acid peptide released during complement activation, binds to C5aR and directs neutrophil chemotaxis and the release of proteolytic enzymes and superoxide (7). C5a binds to both the transmembrane bundle and the amino terminus of C5aR (8, 9), and other binding sites in the extracellular l...

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“…The G-protein-coupled receptor superfamily comprises the largest class of molecules involved in signal transduction across the plasma membrane, thus providing a mechanism of communication between the exterior and the interior of the cell (12,14) and represents *1% of the mammalian genome (15). It is estimated that up to 50% of clinically prescribed drugs act as either agonists or antagonists at GPCRs which points out their immense therapeutic potential (16). The serotonin 1A (5-HT 1A ) receptor is an important representative of this large family of receptors and is the most extensively studied of the serotonin receptors for a number of reasons (17,18).…”

Section: Introductionmentioning

confidence: 99%

Membrane Protein Solubilization: Recent Advances and Challenges in Solubilization of Serotonin1A Receptors

Kalipatnapu

Chattopadhyay

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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SummarySolubilization of integral membrane proteins is a process in which the proteins and lipids that are held together in native membranes are suitably dissociated in a buffered detergent solution. The controlled dissociation of the membrane results in formation of small protein and lipid clusters that remain dissolved in the aqueous solution. Effective solubilization and purification of membrane proteins, especially heterologously-expressed proteins in mammalian cells in culture, in functionally active forms represent important steps in understanding structure-function relationship of membrane proteins. In this review, critical factors determining functional solubilization of membrane proteins are highlighted with the solubilization of the serotonin 1A receptor taken as a specific example.IUBMB Life, 57: 505 -512, 2005

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Activation of G-protein-coupled receptors: a common molecular mechanism

Cited by 172 publications

References 62 publications

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

Genetic Analysis of the First and Third Extracellular Loops of the C5a Receptor Reveals an Essential WXFG Motif in the First Loop

Membrane Protein Solubilization: Recent Advances and Challenges in Solubilization of Serotonin1A Receptors

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