Hoelzer Sandbox
Madison West High School 2007-2008 SMART Team ProjectMadison West High School 2007-2008 SMART Team Project
|
AbstractAbstract
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.