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Model of the whole rat AT1 receptor and the ligand-binding site

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Abstract

We present a three-dimensional model of the rat type 1 receptor (AT1) for the hormone angiotensin II (Ang II). Ang II and the AT1 receptor play a critical role in the cell-signaling process responsible for the actions of renin–angiotensin system in the regulation of blood pressure, water-electrolyte homeostasis and cell growth. Development of improved therapeutics would be significantly enhanced with the availability of a 3D-structure model for the AT1 receptor and of the binding site for agonists and antagonists. This model was constructed using a combination of computation and homology-modeling techniques starting with the experimentally determined three-dimensional structure of bovine rhodopsin (PDB#1F88) as a template. All 359 residues and two disulfide bonds in the rat AT1 receptor have been accounted for in this model. Ramachandran-map analysis and a 1 nanosecond molecular dynamics simulation of the solvated receptor with and without the bound ligand, Ang II, lend credence to the validity of the model. Docking calculations were performed with the agonist, Ang II and the antihypertensive antagonist, losartan.

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Acknowledgements

We thank Dr. Valentin Gogonea, Cleveland State University for useful comments on the manuscript, the members of the Karnik laboratory for valuable discussions and Robin Lewis for manuscript preparation. The R01 (HL57470) grant award to SK from the National Institutes of Health supported this work and SK is an established Investigator of the American Heart Association.

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  1. Department of Molecular Cardiology at Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Camelia Baleanu-Gogonea & Sadashiva Karnik

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  1. Camelia Baleanu-Gogonea
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  2. Sadashiva Karnik
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Correspondence to Sadashiva Karnik.

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Baleanu-Gogonea, C., Karnik, S. Model of the whole rat AT1 receptor and the ligand-binding site. J Mol Model 12, 325–337 (2006). https://doi.org/10.1007/s00894-005-0049-z

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