Distinct binding mode of 125I-AngII to AT1 receptor without the Cys18-Cys274 disulfide bridge

Martin, Renan Paulo; Rodrigues, Eliete S.; Pacheco, Nelson A.S.; Correa, Silvana Aparecida Alves; Oliveira, Sérgio Ferreira de; Oliveira, Laerte; Nakaie, Clóvis R.; Shimuta, Suma I.

doi:10.1016/j.regpep.2009.07.015

Cited by 2 publications

(2 citation statements)

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“…As Hcy has a very high propensity to form disulfide bonds (S–S bonds) with proteins 32 , and the disulfide bonds of the AT1 receptor are reported to be regulated by thiol antioxidants 25 , we speculated that Hcy might interact with the AT1 receptor disulfide bridges. The four cysteines in the extracellular loops (ECLs) of the AT1 receptor form two disulfide bridges (Cys 18 with Cys 274 and Cys 101 with Cys 180 ), and these disulfide bridges have been reported to affect the binding affinity of Ang II and losartan, respectively 26 , 33 . Thus, the two cysteines forming one disulfide bond were mutated together, producing two mutants, each deficient in one disulfide bridge (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5h ). The Cys 18 and Cys 274 mutation has been reported to induce constitutive activation of the AT1 receptor, while disruption of the Cys 101 –Cys 180 disulfide bridge also inhibits the Ang II binding affinity 33 – 35 . Of interest, although the activation by Ang II was blocked in both mutations, the effect of Hcy in inducing NFAT signaling was not affected (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

et al. 2018

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Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg167 and Cys289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

et al. 2018

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Novel Molecular Angiotensin Converting Enzyme and Angiotensin Receptor Imaging Techniques

Shirani

Dilsizian

2014

Curr Cardiol Rep

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Angiotensin II (AII), an octapeptide member of the renin-angiotensin system (RAS), is formed by the enzyme angiotensin converting enzyme (ACE) and exerts adverse cellular effects through an interaction with its type 1 receptor (AT1R). Both ACE inhibitors and angiotensin receptor blockers (ARB) mitigate the vasoconstrictive, proliferative, proinflammatory, proapoptotic, and profibrotic effects of AII and are widely used as effective anti-remodeling agents in clinical practice. Prediction of individual response to these agents, however, remains problematic and is influenced by many factors including race, gender, and genotype. In addition, systemic and tissue RAS activity do not correlate closely. This report summarizes the results of on-going attempts to noninvasively determine tissue ACE activity and AT1R expression using novel nuclear tracers. It is hoped that the availability of such imaging techniques improve treatment of heart failure through more selective pharmacologic intervention and better dose titration of available drugs.

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Distinct binding mode of 125I-AngII to AT1 receptor without the Cys18-Cys274 disulfide bridge

Cited by 2 publications

References 25 publications

Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

Novel Molecular Angiotensin Converting Enzyme and Angiotensin Receptor Imaging Techniques

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