Hoelzer Sandbox
Madison West High School SMART Team Molecular Story of β2-Adrenergic ReceptorMadison West High School SMART Team Molecular Story of β2-Adrenergic Receptor
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Abstract for Our ProjectAbstract for Our Project
G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins coded by the human genome. GPCRs are important for signal transduction with the general structural characteristic of a plasma membrane receptor with seven transmembrane segments. More than 50% of human therapeutics act on GPCRs, but these drugs only interact with a fraction of the GPCRs. One example of a GPCR targeted by pharmaceutical companies is the β2-adrenergic receptor. Adrenergic receptors are found throughout the body and are triggered by the hormone epinephrine (also known as adrenaline, hence the name adrenergic). When epinephrine binds to the receptors, it causes a slight conformational change within the receptor. This change then triggers activation of a G-protein (proteins that bind GTP and are coupled to the receptor on the cytoplasmic side of the receptor) causing dissociation of the G-protein from the receptor). Through the transfer of GTP, G-protein activates an enzyme that converts ATP into cyclic AMP, which induces a response within the cell (for example, muscle contraction if the receptor is located on a muscle cell). When this signal transduction event functions normally in the body, it helps regulate heart rate and blood pressure and is important for the “fight or flight” response. It is important medically to be able to manipulate these functions in cases of high blood pressure or heart failure through the use of beta blockers, a medicine designed to bind to adrenergic receptors, thus inhibiting the binding of epinephrine, and resulting in a lack of effect of the hormone on the body. We have used rapid prototyping technology to model the interaction of the human β2-adrenergic receptor with the beta blocker, carazolol. The structure is dominated by seven alpha helices and is representative of the structure of GPCRs. By modeling the β2-adrenergic receptor, we hope to better understand GPCRs as well as understand the mechanism of hormone/drug binding, which will aid in developing better drug treatments.
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Creating the Physical Model of the β2-adrenergic receptorCreating the Physical Model of the β2-adrenergic receptor
We started our physical model of the β2-adrenergic receptor in the protein viewing software Rasmol. The default format for a newly opened .pdb file in Rasmol is a thin wireframe . Our SMART Team wanted to focus on the binding portion of the receptor so we only displayed residues 29-230 and 263-342 in backbone format . Next, we colored the alpha helices green, the turns gray, the first amino acid on the N-terminal end magenta, and the last amino acid on the C-terminal end blue. . Then we added the cholesterol ligands located on the side of the seven helix portion of the protein. We displayed them in ball and stick format and colored them red . One of the most important portions of our model is the beta blocker Carazolol which we displayed in ball and stick format and colored orange . The last step was adding the main sidechains involved in the binding of the beta blocker. We displayed Phe 193, Trp 286, Phe 289, and Phe 290 in ball and stick format and colored them cyan . Once our model designs were complete in Rasmol, we added monitor lines to help support the model for building and saved the 3D file for printing . Our model was built by the Center for BioMolecular Modeling at the Milwaukee School of Engineering where they are able to use rapid prototyping technology to build any model designed in the computer environment.
Our Poster and Presentation at the 2008 ASBMB Meeting in San Diego, CAOur Poster and Presentation at the 2008 ASBMB Meeting in San Diego, CA
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