Group:SMART:P-glycoprotein: Why Cancer Drugs Fail: Difference between revisions

==Our Model==

Because P-glycoprotein is embedded in the cell membrane, it contains both hydrophilic and hydrophobic regions. If you look closely at the protein model, you will notice a band of violet or a hydrophobic band. The hydrophobic band is the region of the protein that is embedded in the cell membrane (since the inside of the cell membrane is hydrophobic and the outside of the cell membrane is hydrophilic). Both the hydrophobic and hydrophilic regions are critical in P-glycoprotein’s function in transporting drugs out of the cell. The active site residues that are important for the transport of Verapamil are highlighted with the color <font color=lime><b>green</b></font>. These residues are <i>H60, A63, L64, S218, I302, L335, A338, F724, I864, G868, F938, T941, L971, V978, G980,</i> and <i>A981</i>. The Nucleotide Binding Domains (NBDs), which are highlighted in <font color=gold><b>yellow</b></font>, are important because after binding to ATP, the conformation of the protein changes. By  changing the conformation of the protein, drugs are transported out of the cell. P-glycoprotein is also an active transporter because it requires energy of ATP in order to transports drugs out of cells.

Not shown on the model are flaps(--) that aid in guiding drugs into the cavity of the protein. Once the drug reaches the cavity, it would bind to specific residues (that are similar to those Verapamil residues (in green). Once ATP binds to the NBDs of the protein, the protein would change its conformation, taking the drugs out. The original conformation of the protein is an upside down V. When ATP binds to the NBDs, the NBDs close up, and the tip of the protein opens up, changing the conformation of the protein in the shape of a V.

-- The flaps are not shown because they are too fragile to crystallize.