Biology Faculty Proceedings, Presentations, Speeches, Lectures

Developing 3-D Molecular Models to Highlight the Angiotensin II Type 1 Receptor and Olmesartan Binding for Medical and Educational Applications

Event Name/Location

Experimental Biology, Chicago, Illinois, April 22-26, 2017

Presentation Date

4-2017

Document Type

Conference Proceeding

Description

Blood pressure regulation through the renin-angiotensin system (RAS) is mediated through the activation and inhibition of angiotensin II (AngII) from its precursor angiotensin I (AngI). Activation of AngII leads to vasoconstriction, resulting in an increase in blood pressure, while AngII inhibition prevents vasoconstriction, causing a decrease in blood pressure. In humans, AngII binds to two subtypes of angiotensin G protein-coupled receptors (GPCRs): AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R). Almost all physiological and pathophysiological effects of AngII are mediated by AT1R, while the function of AT2R remains largely unknown. AT1R receptor blockers (ARBs), or sartans, are non-peptide antagonists that act on behalf of the RAS cascade to inhibit vasoconstriction, thereby lowering blood pressure. Benicar™ is the most common brand of olmesartan, and in this study the interaction of this type of ARB with the angiotensin II AT1 receptor was modeled to depict the effects of angiotensin receptor blockers. The CBM-SMART team (Center for Biomolecular Modeling - Students Modeling A Research Topic) at Nova Southeastern University used 3-D modeling and printing technology to examine structure and function relationships of the receptor and its antagonist. Details of the AT1R-olmesartan structure from the Protein Data Bank file, 4ZUD, were imported into Jmol, a protein visualization software. Specific program commands were utilized in Jmol to manipulate the original file into a format that was later able to be 3-D printed in order to create an instructional molecular model. The olmesartan anchors on the AT1 receptor were identified and noted on the model, consisting of amino acid residues Tyr35, Trp84, and Arg167. Additionally, three extracellular loops, as well as two disulfide bonds that contribute to the shape of the extracellular side of AT1R were emphasized. The amino acid residues Asp74, Asn111, and Asn 295 were highlighted in order to indicate the sodium-ion binding pocket which is responsible for the intramolecular hydrogen bonding that regulates activation of AT1R. Developing 3-D molecular models in this way is a relatively inexpensive process to visually represent important biological relationships that can be useful for students, professors, and physicians trying to understand complex molecular pathways.

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