A review of mutagenesis studies of angiotensin II type 1 receptor, the three-dimensional receptor model in search of the agonist and antagonist binding site and the hypothesis of a receptor activation mechanism

1997 ◽  
Vol 15 (7) ◽  
pp. 703-714 ◽  
Author(s):  
Yoshihisa Inoue ◽  
Norifumi Nakamura ◽  
Tadashi Inagami
Keyword(s):  
Angiotensin Ii ◽  
Binding Site ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Receptor Model ◽  
Agonist And Antagonist ◽  
Antagonist Binding

scholarly journals OR24-01 Mutational Study of the GPR119 Receptor Binding Site

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Matthew D Rosales ◽  
Frank Dean ◽  
Evangelia Kotsikorou
Keyword(s):  
Hydrogen Bonding ◽  
Binding Site ◽  
Specific Activity ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Receptor Model ◽  
Wild Type

Abstract The GPR119 receptor, a class A G-protein coupled receptor located in the pancreatic β cells, induces insulin production when activated. Due to its specific activity, the pharmaceutical industry has identified GPR119 as a target for the treatment for type 2 diabetes. The lack of a GRP119 crystal structure has hindered the study of the receptor so our laboratory developed GPR119 active and inactive homology models. Docking studies with the inactive receptor model indicated that two leucine residues facing the binding pocket, L5.43(169) and L6.52(242), may be involved in ligand activation. Additionally, a serine at the extracellular end of the pocket, S1.32(4), may help orient of the ligand in the binding pocket via hydrogen bonding. To gain further insight into the role of these residues and the receptor activation mechanism, molecular dynamics (MD) simulations and in vitro cAMP assays of the wild type and mutant receptors were employed. The software NAMD employing the CHARMM force field was used to carry out MD simulations of the active receptor model bound with the agonist AR231453 embedded in a hydrated lipid bilayer. Preliminary results indicate that L6.52(242), located on transmembrane helix (TMH) 6, does not face directly into the binding site and does not interact with the ligand, while L5.43(169), located on TMH5, does face into the binding site, potentially interacting directly with the ligand. Also, S1.32(4), because of its extracellular location, is solvated instead of interacting with the ligand. The in vitro studies overall support the MD simulations. The mutations L6.52(242)M and L6.52(242)A appear to have minimal to no effect on agonist-induced cAMP production, compared to the wild type. In contrast, the L5.43(169)M and L5.43(169)A mutations decrease the potency of activation by AR231453, indicating that L5.43(169) changes the shape of the binding pocket, affecting ligand binding and activation. Finally, the cAMP assays show that the S1.32(4)A mutant also shows decreased activity compared to the wild type, implying that the ligand may be losing a hydrogen bonding interaction when S1.32(4) is mutated to alanine.

Mutational analysis of neurokinin receptor function

1995 ◽  
Vol 73 (7) ◽  
pp. 860-865 ◽  
Author(s):  
Tung Ming Fong ◽  
Ruey-Ruey C. Huang ◽  
Hong Yu ◽  
Dennis Underwood ◽  
Margaret A. Cascieri ◽  
...  
Keyword(s):  
Binding Site ◽  
Mutational Analysis ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Site Directed Mutagenesis ◽  
Receptor Interaction ◽  
Three Dimensional Model ◽  
Neurokinin Receptor ◽  
Agonist And Antagonist ◽  
Key Residues

The interactions of the NK1 receptor with peptide agonists or nonpeptide antagonists have been investigated by site-directed mutagenesis and computer modeling. At least 10 residues in the extracellular and transmembrane regions of the receptor are required for the binding of many peptide agonists. The C-terminal amide of peptide agonists is likely to be bound near Asn-85. Residues likely to be involved in the subsequent receptor activation include Glu-78 and Tyr-205. The binding site for nonpeptide antagonists can be defined by at least five residues in transmembrane helices 4–7, and primary contacts between key residues and quinuclidine antagonists have been assigned based on CP-96,345 and its analogs. Analyses of the wild-type and mutant NK1 and NK2 receptors, intact and truncated peptides, and various antagonists suggest that the agonist and antagonist binding sites overlap spatially, even though agonists and antagonists do not interact with the same set of residues on the receptor. Mapping the ligand binding site not only allows us to better understand the ligand–receptor interaction and antagonism but also leads to a refined three-dimensional model of the NK1 receptor.Key words: receptor, substance P, agonist, antagonist, mutagenesis.

A novel mechanism of mechanical stress-induced angiotensin II type 1–receptor activation without the involvement of angiotensin II

2007 ◽  
Vol 377 (4-6) ◽  
pp. 393-399 ◽  
Author(s):  
Noritaka Yasuda ◽  
Hiroshi Akazawa ◽  
Yingjie Qin ◽  
Yunzeng Zou ◽  
Issei Komuro
Keyword(s):  
Angiotensin Ii ◽  
Mechanical Stress ◽  
Receptor Activation

Lipid signal transduction pathways in angiotensin II type 1 receptor-transfected fibroblasts

1995 ◽  
Vol 269 (2) ◽  
pp. C435-C442 ◽  
Author(s):  
Y. Wen ◽  
M. C. Cabot ◽  
E. Clauser ◽  
S. L. Bursten ◽  
J. L. Nadler
Keyword(s):  
Signal Transduction ◽  
Angiotensin Ii ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Ang Ii ◽  
Vascular Type ◽  
Lipid Signal ◽  
Fibroblast Line

A stable Chinese hamster ovary fibroblast line expressing the rat vascular type 1a angiotensin II (ANG II) receptor was used to study the lipid-derived signal transduction pathways elicited by type 1a ANG II receptor activation. ANG II caused a biphasic and dose-dependent increase in diacylglycerol (DAG) accumulation with an initial peak at 15 s (181 +/- 11% of control, P < 0.02) and a second sustained peak at 5-10 min (214 +/- 10% of control, P < 0.02). The late DAG peak was derived from phosphatidylcholine (PC), and the formation was blocked by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. ANG II also increased phosphatidic acid (PA) production nearly fourfold by 7.5 min. In the presence of ethanol, ANG II markedly increased phosphatidylethanol (PEt) formation, indicating activation of phospholipase D (PLD). ANG II was shown to increase the mass of three separate PA species, one of which apparently originated from DAG kinase action on PC-phospholipase C (PLC)-produced DAG, providing evidence for PC-PLC activity. ANG II also formed a third PA species, which originated neither from PLD nor from DAG kinase. These results demonstrate that multiple lipid signals propagated via collateral stimulation of PLC and PLD are generated by specific activation of the vascular type 1a ANG II receptor.

scholarly journals Distinct Conformations of the Corticotropin Releasing Factor Type 1 Receptor Adopted following Agonist and Antagonist Binding Are Differentially Regulated

2005 ◽  
Vol 280 (12) ◽  
pp. 11560-11568 ◽  
Author(s):  
Stephen J. Perry ◽  
Sachiko Junger ◽  
Trudy A. Kohout ◽  
Sam R.J. Hoare ◽  
R. Scott Struthers ◽  
...  
Keyword(s):  
Corticotropin Releasing Factor ◽  
Agonist And Antagonist ◽  
Antagonist Binding ◽  
Factor Type

scholarly journals An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

2010 ◽  
Vol 80 (1) ◽  
pp. 86-94 ◽  
Author(s):  
Marie Mi Bonde ◽  
Rong Yao ◽  
Jian-Nong Ma ◽  
Srinivasan Madabushi ◽  
Stig Haunsø ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Trace Analysis ◽  
Receptor Activation ◽  
Evolutionary Trace ◽  
Evolutionary Trace Analysis

Lack of heterologous receptor desensitization induced by angiotensin II type 1 receptor activation in isolated normal rat thoracic aorta

2011 ◽  
Vol 54 (1-2) ◽  
pp. 29-35 ◽  
Author(s):  
Teresa Pérez ◽  
Ruth M. López ◽  
Pedro López ◽  
Carlos Castillo ◽  
Enrique F. Castillo
Keyword(s):  
Angiotensin Ii ◽  
Thoracic Aorta ◽  
Receptor Activation ◽  
Receptor Desensitization ◽  
Rat Thoracic Aorta ◽  
Normal Rat

Cysteinyl leukotriene-dependent [Ca2+]iresponses to angiotensin II in cardiomyocytes

2003 ◽  
Vol 284 (4) ◽  
pp. H1269-H1276 ◽  
Author(s):  
Pinggang Liu ◽  
Derek A. Misurski ◽  
Venkat Gopalakrishnan
Keyword(s):  
Angiotensin Ii ◽  
Single Cells ◽  
Receptor Activation ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Neonatal Rat Cardiomyocytes ◽  
Cysteinyl Leukotriene

With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca2+ concentration ([Ca2+]i) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT1) antagonist losartan, but not the AT2antagonist PD-123319, attenuated the elevations in [Ca2+]i and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca2+]i but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT1-selective antagonist MK-571 reduced the maximal [Ca2+]i responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D4 (LTD4), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca2+]i elevation to both LTD4and LTC4. These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca2+]i involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca2+]i responses to ANG II and LTD4. Thus AT1 receptor activation by ANG II is linked to CysLT-mediated Ca2+ release from Ins(1,4,5)P3-sensitive intracellular stores to augment direct ANG II-evoked Ca2+ mobilization in rat cardiomyocytes.

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