3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data

Nikiforovich, Gregory V.; Marshall, Garland R.

doi:10.1006/bbrc.2001.5526

Cited by 34 publications

(29 citation statements)

References 54 publications

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“…Stereoview showing regions of the at1 angiotensin receptor involved in ligand binding (red), signal propagation (green), and G protein binding (blue). The residues with atoms shown as spheres are from the crystallographic model of rhodopsin, but their positions were chosen on the basis of a tabulation of important residues in the at1 angiotensin receptor (77). …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Crystallographic Model of Rhodopsin and Its Use in Studies of Other G Protein–Coupled Receptors

Filipek

Teller

Palczewski

et al. 2003

Annu. Rev. Biophys. Biomol. Struct.

122

101

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G protein-coupled receptors (GPCRs) are integral membrane proteins that respond to environmental signals and initiate signal transduction pathways activating cellular processes. Rhodopsin is a GPCR found in rod cells in retina where it functions as a photopigment. Its molecular structure is known from cryo-electron microscopic and X-ray crystallographic studies, and this has reshaped many structure/function questions important in vision science. In addition, this first GPCR structure has provided a structural template for studies of other GPCRs, including many known drug targets. After presenting an overview of the major structural elements of rhodopsin, recent literature covering the use of the rhodopsin structure in analyzing other GPCRs will be summarized. Use of the rhodopsin structural model to understand the structure and function of other GPCRs provides strong evidence validating the structural model.

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Section: Discussionmentioning

confidence: 99%

“…However, it is often difficult to assess the quality and relevance of molecular models. Concerns about the structures of the loops in rhodopsin have been expressed (21,69), as have questions about the validity of the rhodopsin structure as a general template for GPCRs (25,76,77).…”

Section: Assessment Of Alternative Modelsmentioning

confidence: 99%

The Crystallographic Model of Rhodopsin and Its Use in Studies of Other G Protein–Coupled Receptors

Filipek

Teller

Palczewski

et al. 2003

Annu. Rev. Biophys. Biomol. Struct.

122

101

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“…The movements of TMDs 3 and 6 at the cytoplasmic side of the membrane are crucial in the activation of GPCRs (Moukhametzianov et al 2011). The following amino acids from TMDs 2, 3, 4, 5, 6, and 7 are critical in forming the ligand-binding pocket to nestle Ang II: Ser105, Leu112, and Tyr113 in TMD3; Phe249, Trp253, His256, and Thr260 in TMD6; and Phe293, Asn294, Asn295, Cys296, and Leu297 in TMD7 (Nikiforovich & Marshall 2001, Baleanu-Gogonea & Karnik 2006. In addition, the C-terminal region of the second and C-and N-terminal regions of the third cytoplasmic loops and the membraneproximal region of the carboxy-terminal tail (residues 309-318) are implicated in G protein activation.…”

Section: Molecular Specifics Of Ang II Binding and Activation Of The mentioning

confidence: 99%

“…The ligand-binding pocket for the hormone is created with amino acid residues of transmembrane helices 2, 3, 4, 5, 6, and 7 (Boucard et al 2000, Baleanu-Gogonea & Karnik 2006. Structure-activity studies with several analogs of Ang II have shown the importance of Arg 2 , Tyr 4 , His 6 , and Phe 8 and the negatively charged carboxy-terminal region in the biological activity of the deduced conformation for Ang II (Nikiforovich & Marshall 2001, Wilkes et al 2002. Site-directed mutagenesis has led several investigators to suggest that amino acid residues 1-7 define receptor affinity, specificity, and initiation of signal transduction, whereas the amino acid 8 involves receptor agonism.…”

Section: Introductionmentioning

confidence: 99%

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar¹,

Jagadeesh²

2014

Journal of Molecular Endocrinology

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT 1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT 1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT 1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT 1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G proteinindependently through b-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT 1 receptor.

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“…Previous studies have implicated the extracellular-facing portion of TM5 as a region important for ligand binding. A current model proposes a direct contact between Val5 in Ang II and F204 (Nikiforovich and Marshall, 2001). F204 is near K199, a residue known to be involved in agonist and antagonist binding (Noda et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Loss-of-Function Polymorphic Variants of the Human Angiotensin II Type 1 Receptor

Hansen¹,

Haunsø²,

Brann³

et al. 2004

Mol Pharmacol

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The angiotensin II type 1 (AT 1 ) receptor is the primary effector for angiotensin II (Ang II), a key peptide regulator of blood pressure and fluid homeostasis. AT 1 receptors are involved in the pathogenesis of several cardiovascular diseases, including hypertension, cardiac hypertrophy, and congestive heart failure, which are characterized by significant interindividual variation in disease risk, progression, and response to pharmacotherapy. Such variation could arise from genomic polymorphisms in the AT 1 receptor. To pursue this notion, we have pharmacologically characterized seven known and putative nonsynonymous AT 1 receptor variants. Functional analysis using the cell-based assay receptor selection and amplification technology (R-SAT) revealed that three variants (AT 1 -G45R, AT 1 -F204S, and AT 1 -C289W) displayed altered responses to Ang II and other AT 1 receptor agonists and antagonists. Agonist responses to Ang II were absent for AT 1 -G45R and significantly reduced in potency for AT 1 -C289W (11-fold) and AT 1 -F204S (57-fold) compared with the wild-type (WT) receptor. AT 1 -F204S also displayed reduced relative efficacy (57%). Quantitatively similar results were obtained in two additional functional assays, phosphatidyl inositol hydrolysis and extracellular signal-regulated kinase activation. Radioligand binding studies revealed that AT 1 -G45R failed to bind Ang II, whereas cell surface staining clearly showed that it trafficked to the cell surface. AT 1 -C289W and AT 1 -F204S displayed reduced binding affinities of 3-and 5-fold and reduced cell surface expression of 43 and 60% of that observed for the WT receptor, respectively. These data demonstrate that polymorphic variation in the human AT 1 receptor induces loss of functional phenotypes, which may constitute the molecular basis of variability of AT 1 receptor-mediated physiological responses.Angiotensin II type 1 (AT 1 ) receptors (Takayanagi et al., 1992) mediate many of the physiological effects of angiotensin II (Ang II), an endogenous octapeptide that, via the actions of the renin-angiotensin system, serves as one of the pivotal regulators of blood pressure and fluid homeostasis. The AT 1 receptor is a highly conserved seven-transmembrane (7TM) receptor expressed in most tissues, particularly in vascular and renal tissues, where receptor activation leads to vasoconstriction and water retention. The renin-angiotensin system subserves critical pathophysiological roles in several cardiovascular diseases, including hypertension, cardiac hypertrophy, congestive heart failure, diabetic nephropathy,

show abstract

3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data

Cited by 34 publications

References 54 publications

The Crystallographic Model of Rhodopsin and Its Use in Studies of Other G Protein–Coupled Receptors

The Crystallographic Model of Rhodopsin and Its Use in Studies of Other G Protein–Coupled Receptors

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Loss-of-Function Polymorphic Variants of the Human Angiotensin II Type 1 Receptor

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