scholarly journals The Second Transmembrane Domain of the Human Type 1 Angiotensin II Receptor Participates in the Formation of the Ligand Binding Pocket and Undergoes Integral Pivoting Movement during the Process of Receptor Activation

2009 ◽  
Vol 284 (18) ◽  
pp. 11922-11929 ◽  
Author(s):  
Ivana Domazet ◽  
Brian J. Holleran ◽  
Stéphane S. Martin ◽  
Pierre Lavigne ◽  
Richard Leduc ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ligand Binding ◽  
Transmembrane Domain ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Angiotensin Ii Receptor ◽  
Ligand Binding Pocket ◽  
Human Type

scholarly journals Constitutive Activation of the Angiotensin II Type 1 Receptor Alters the Spatial Proximity of Transmembrane 7 to the Ligand-binding Pocket

2003 ◽  
Vol 278 (38) ◽  
pp. 36628-36636 ◽  
Author(s):  
Antony A. Boucard ◽  
Marise Roy ◽  
Marie-Ève Beaulieu ◽  
Pierre Lavigne ◽  
Emanuel Escher ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Spatial Proximity ◽  
Ligand Binding Pocket ◽  
Constitutive Activation

scholarly journals Analysis of the Third Transmembrane Domain of the Human Type 1 Angiotensin II Receptor by Cysteine Scanning Mutagenesis

2004 ◽  
Vol 279 (49) ◽  
pp. 51415-51423 ◽  
Author(s):  
Stéphane S. Martin ◽  
Antony A. Boucard ◽  
Martin Clément ◽  
Emanuel Escher ◽  
Richard Leduc ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transmembrane Domain ◽  
Angiotensin Ii Receptor ◽  
The Third ◽  
Human Type ◽  
Cysteine Scanning ◽  
Cysteine Scanning Mutagenesis

scholarly journals Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization

2008 ◽  
Vol 78 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Katy Rivard ◽  
Pierre Paradis ◽  
Mona Nemer ◽  
Céline Fiset
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Ii Receptor ◽  
Human Type

scholarly journals Structural basis of bile acid receptor activation and Gs coupling

2020 ◽  
Author(s):  
Fan Yang ◽  
Chunyou Mao ◽  
Lulu Guo ◽  
Jingyu Lin ◽  
Qianqian Ming ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ligand Binding ◽  
Bile Acids ◽  
G Protein ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Structural Features ◽  
Ligand Binding Pocket ◽  
Bile Acid Receptor ◽  
Key Residues

AbstractG protein-coupled bile acid receptor (GPBAR) is a membrane receptor that senses bile acids to regulate diverse functions through Gs activation. Here, we report the cryo-EM structures of GPBAR–Gs complexes stabilized by either high-affinity P395 or the semisynthesized bile acid derivative INT-777 at 3-Å resolution. These structures revealed a large oval-shaped ligand pocket with several sporadic polar groups to accommodate the amphipathic cholic core of bile acids. A fingerprint of key residues recognizing diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias property were identified through structural analysis and mutagenesis studies. Moreover, structural comparison of GPBAR with other GPCRs uncovered an atypical mode of receptor activation and G-protein– coupling, featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only provides unique structural features of GPBAR in bile acid recognition, allosteric effects and biased signaling, but also suggests that distinct allosteric connecting mechanisms between the ligand binding pocket and the G protein binding site exist in the GPCR superfamily.

Differential Mapping of the Amino Acids Mediating Agonist and Antagonist Coordination with the Human Thromboxane A2 Receptor Protein.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3571-3571
Author(s):  
Fadi T. Khasawneh ◽  
Jin-Sheng Huang ◽  
Joseph W. Turek ◽  
Guy C. Le Breton
Keyword(s):  
Amino Acids ◽  
Ligand Binding ◽  
Functional Response ◽  
Transmembrane Domain ◽  
Thromboxane A2 ◽  
Binding Pocket ◽  
Receptor Protein ◽  
Ligand Binding Pocket ◽  
Thromboxane A2 Receptor ◽  
Ligand Coordination

Abstract Despite the well-documented involvement of thromboxane A2 receptor (TPR) signaling in the pathogenesis of thrombotic diseases, there are currently no rationally-designed antagonists available for clinical use. To a large extent this derives from a lack of knowledge regarding the topography of the TPR ligand binding pocket. On this basis, the purpose of the current study was to identify the specific amino acid residues in the TPR protein which regulate ligand coordination and binding. The sites selected for mutation reside within or in close proximity to a region we previously defined as a TPR ligand binding site, i.e., the C-terminus of the second extracellular loop and the leading edge of the fifth transmembrane domain. Mutation of these residues caused varying effects on the TPR-ligand coordination process. Specifically, the D193A mutant lacked both SQ29,548 (antagonist) binding and U46619 (agonist)-induced calcium mobilization. Three other mutants, F184Y, T186A and S191T, discriminated between SQ29,548 binding and the U46619-mediated functional response. Furthermore, these mutants also revealed a divergence in the binding of two structurally different antagonists, SQ29,548 and BM13.505. Conversely, two separate mutants which exhibited SQ29,548 binding activity yielded either a normal (F196Y) or reduced (S201T) U46619 response. Finally, mutation of other residues directly adjacent to those described above, e.g., E190A and F200A, produced no detectable effects on either SQ29,548 binding or the U46619-induced functional response. In summary, these results identify key amino acids involved in TPR ligand coordination and demonstrate that TPR-specific ligands do not necessarily interact with the same residues in the ligand-binding pocket.

scholarly journals Rhodopsin: Structural Basis of Molecular Physiology

2001 ◽  
Vol 81 (4) ◽  
pp. 1659-1688 ◽  
Author(s):  
Santosh T. Menon ◽  
May Han ◽  
Thomas P. Sakmar
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Critical Evaluation ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Structural Basis ◽  
Molecular Physiology ◽  
Movement Model ◽  
Ligand Binding Pocket ◽  
Cytoplasmic Surface

The crystal structure of rod cell visual pigment rhodopsin was recently solved at 2.8-Å resolution. A critical evaluation of a decade of structure-function studies is now possible. It is also possible to begin to explain the structural basis for several unique physiological properties of the vertebrate visual system, including extremely low dark noise levels as well as high gain and color detection. The ligand-binding pocket of rhodopsin is remarkably compact, and several apparent chromophore-protein interactions were not predicted from extensive mutagenesis or spectroscopic studies. The transmembrane helices are interrupted or kinked at multiple sites. An extensive network of interhelical interactions stabilizes the ground state of the receptor. The helix movement model of receptor activation, which might apply to all G protein-coupled receptors (GPCRs) of the rhodopsin family, is supported by several structural elements that suggest how light-induced conformational changes in the ligand-binding pocket are transmitted to the cytoplasmic surface. The cytoplasmic domain of the receptor is remarkable for a carboxy-terminal helical domain extending from the seventh transmembrane segment parallel to the bilayer surface. Thus the cytoplasmic surface appears to be approximately the right size to bind to the transducin heterotrimer in a one-to-one complex. Future high-resolution structural studies of rhodopsin and other GPCRs will form a basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction.

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