scholarly journals Modelo molecular teórico del receptor serotoninérgico 5HT2A acoplado a proteína G

2012 ◽  
Vol 17 (2) ◽  
pp. 119
Author(s):  
Rafael Eduardo Malagón Bernal ◽  
Manuel Alejandro Fernández Navas ◽  
Orlando Emilio Acevedo Sarmiento
Keyword(s):  
Theoretical Model ◽  
G Protein ◽  
Tertiary Structure ◽  
Homo Sapiens ◽  
Molecular Model ◽  
Ramachandran Plot ◽  
Bovine Rhodopsin ◽  
Protein Receptor ◽  
G Protein Coupled ◽  
Hydrophobicity Profile

<strong>Objective</strong> Build a theoretical molecular model of the tertiary structure of the Homo sapiens 5HT2A receptor from experimentally obtained structures as templates. <strong>Materials</strong> <strong>and methods</strong> In the construction of the theoretical model we considered the protocol established by Ballesteros and Weinstein for the construction of the G-protein coupled receptor, by the alignment of the amino acid sequence, hydrophobicity profiles, refinement of loops by spatial restrictions and energy minimization with the force field OPLS_2005. <strong>Results</strong> The resulting model was validated by the Ramachandran plot with 91.7% of amino acids within the limits set for angles phi and psi and a RMSD of 0.95 Å with respect to bovine rhodopsin. <strong>Conclusions</strong> We obtained a validated theoretical model useful in studies of ligand-receptor docking.<br /><strong>Key words</strong>: G protein receptor, hydrophobicity profile, Ramachandran plot, orthosteric site, molecular modelling.

scholarly journals G protein-coupled receptors--recent advances.

2012 ◽  
Vol 59 (4) ◽  
Author(s):  
Dorota Latek ◽  
Anna Modzelewska ◽  
Bartosz Trzaskowski ◽  
Krzysztof Palczewski ◽  
Sławomir Filipek
Keyword(s):  
G Protein ◽  
Biochemical Characterization ◽  
Membrane Receptors ◽  
Signaling Cascades ◽  
Protein Signaling ◽  
Partial Activation ◽  
Bovine Rhodopsin ◽  
G Protein Coupled ◽  
Multiple Ligand

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

scholarly journals First Principles Predictions of the Structure and Function of G-Protein-Coupled Receptors: Validation for Bovine Rhodopsin

2004 ◽  
Vol 86 (4) ◽  
pp. 1904-1921 ◽  
Author(s):  
Rene J. Trabanino ◽  
Spencer E. Hall ◽  
Nagarajan Vaidehi ◽  
Wely B. Floriano ◽  
Victor W.T. Kam ◽  
...  
Keyword(s):  
G Protein ◽  
First Principles ◽  
Structure And Function ◽  
G Protein Coupled Receptors ◽  
Bovine Rhodopsin ◽  
And Function ◽  
G Protein Coupled

scholarly journals Desensitization of the Neurokinin-1 Receptor (NK1-R) in Neurons: Effects of Substance P on the Distribution of NK1-R, Gαq/11, G-Protein Receptor Kinase-2/3, and β-Arrestin-1/2

1998 ◽  
Vol 9 (8) ◽  
pp. 2305-2324 ◽  
Author(s):  
Karen McConalogue ◽  
Carlos U. Corvera ◽  
Patrick D. Gamp ◽  
Eileen F. Grady ◽  
Nigel W. Bunnett
Keyword(s):  
Plasma Membrane ◽  
Substance P ◽  
G Protein ◽  
Neurokinin 1 Receptor ◽  
Protein Receptor ◽  
Early Endosomes ◽  
Receptor Kinases ◽  
Neurokinin 1 ◽  
G Protein Coupled ◽  
Neurotransmitter Substance

Observations in reconstituted systems and transfected cells indicate that G-protein receptor kinases (GRKs) and β-arrestins mediate desensitization and endocytosis of G-protein–coupled receptors. Little is known about receptor regulation in neurons. Therefore, we examined the effects of the neurotransmitter substance P (SP) on desensitization of the neurokinin-1 receptor (NK1-R) and on the subcellular distribution of NK1-R, Gαq/11, GRK-2 and -3, and β-arrestin-1 and -2 in cultured myenteric neurons. NK1-R was coexpressed with immunoreactive Gαq/11, GRK-2 and -3, and β-arrestin-1 and -2 in a subpopulation of neurons. SP caused 1) rapid NK1-R–mediated increase in [Ca2+]i, which was transient and desensitized to repeated stimulation; 2) internalization of the NK1-R into early endosomes containing SP; and 3) rapid and transient redistribution of β-arrestin-1 and -2 from the cytosol to the plasma membrane, followed by a striking redistribution of β-arrestin-1 and -2 to endosomes containing the NK1-R and SP. In SP-treated neurons Gαq/11 remained at the plasma membrane, and GRK-2 and -3 remained in centrally located and superficial vesicles. Thus, SP induces desensitization and endocytosis of the NK1-R in neurons that may be mediated by GRK-2 and -3 and β-arrestin-1 and -2. This regulation will determine whether NK1-R–expressing neurons participate in functionally important reflexes.

scholarly journals Improved Antibacterial Host Defense and Altered Peripheral Granulocyte Homeostasis in Mice Lacking the Adhesion Class G Protein Receptor CD97

2006 ◽  
Vol 75 (3) ◽  
pp. 1144-1153 ◽  
Author(s):  
Tao Wang ◽  
Linhua Tian ◽  
Makoto Haino ◽  
Ji-Liang Gao ◽  
Ross Lake ◽  
...  
Keyword(s):  
Bone Marrow ◽  
G Protein ◽  
Dermatan Sulfate ◽  
Systemic Infection ◽  
Cell Types ◽  
Wild Type ◽  
Protein Receptor ◽  
Alternatively Spliced ◽  
The Difference ◽  
G Protein Coupled

ABSTRACT CD97 is a member of the adhesion family of G protein-coupled receptors. Alternatively spliced forms of CD97 bind integrins α5β1 and αvβ3, decay accelerating factor, or dermatan sulfate. CD97 is expressed on myeloid cells at high levels and a variety of other cell types at lower levels. Little is known about the physiological function of CD97. To begin dissecting the function of CD97, we evaluated the immune response of CD97 null mice to systemic infection by Listeria monocytogenes. CD97 null mice were significantly more resistant to listeriosis than matched wild-type mice. A major determinant of the difference in survival appeared to be the comparatively more robust accumulation of granulocytes in the blood and in infected livers of CD97 null mice within 18 h of inoculation, correlating with a decrease in the number of bacteria. CD97 null mice also displayed a mild granulocytosis in the nonchallenged state. Because there is a strong suggestion that CD97 functions in an adhesive capacity, we examined the migratory properties of granulocytes in CD97 null mice. In chimeric animals, CD97 null and wild-type granulocytes migrated similarly, as determined by inflammation-induced emigration from the bone marrow and accumulation in the peritoneum. Granulocyte development in the bone marrow of CD97 null mice was comparable to that of wild-type mice, and CD97 deficiency did not appear to stimulate granulocytosis secondary to peripheral inflammation and resultant granulocyte colony-stimulating factor induction, unlike various other models of adhesion deficiencies. Our results suggest that CD97 plays a role in peripheral granulocyte homeostasis.

Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors

2007 ◽  
Vol 35 (4) ◽  
pp. 717-720 ◽  
Author(s):  
M. Wheatley ◽  
J. Simms ◽  
S.R. Hawtin ◽  
V.J. Wesley ◽  
D. Wootten ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Peptide Hormone ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Ligand Selectivity ◽  
Extracellular Loops ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V1aR (V1a vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg8]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V1aR, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

The third extracellular loop of G-protein-coupled receptors: more than just a linker between two important transmembrane helices

2004 ◽  
Vol 32 (6) ◽  
pp. 1048-1050 ◽  
Author(s):  
Z. Lawson ◽  
M. Wheatley
Keyword(s):  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Transmembrane Helices ◽  
Ligand Selectivity ◽  
Interaction Sites ◽  
Amine Neurotransmitters ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins, which mediate their effects by coupling with G-proteins. Despite responding to a range of very diverse stimuli, these receptors exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The hydrophobic environment formed by the cluster of TM helices is functionally important. For example, the 11-cis retinal chromophore of rhodopsin forms a protonated Schiff base linkage to a lysine in TM7, deep within the helical bundle, and small ligands, such as amine neurotransmitters and non-peptide analogues of peptide hormones, also bind within the corresponding region of their cognate receptors. In addition, activation of GPCRs involves relative movement of TM helices to present G-protein interaction sites across the intracellular face of the receptor. Consequently, it might be assumed that the ECLs of the GPCR are inert peptide linkers that merely connect important TM helices. Focusing on ECL3 (third ECL), it is becoming increasingly apparent that this extracellular domain can fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

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