Group:SMART:P-glycoprotein: Why Cancer Drugs Fail
Abraham Lincoln High School, San Francisco CA, SMART TeamAbraham Lincoln High School, San Francisco CA, SMART Team
Team members: Tiffany Cai, Pauline Chan, Maggie Chang, Tina Chen, Desiree Chiu, Jeffrey Chum, Jane Hwang, Nancy Kong, Grace Wang
"Poster Team:" Tiffany Cai, Tina Chen
"Model Team:" Jane Hwang, Nancy Kong, Grace Wang
"Abstract Team:" Pauline Chan, Desiree Chiu
"What is P-gp Team:" Maggie Chang, Jeffrey Chum
Teacher: Mr. Richard Gin
UCSF: Anita Grover (mentor), Ben Koo, Kurt Giles, Sabine Jeske
AbstractAbstract
P-gp is an efflux drug transporter located in the cell membrane of the cell. It transports foreign and unfamiliar substances out of the cell, protecting the body from harmful toxins that stay in the bloodstream. An example would be cleansing toxins from the small intestine when consuming food that may have gone bad. In this case, P-gp would be acting on behalf of our benefit. However, in cancerous cells, P-gp is the main factor that stops treatment from working against cancer. It causes 90% of chemotherapy to fail in patients. Although the drug may be good for the body, P-gp is unable to recognize the drug so it pushes it out of the cell once it enters. P-gp is why most cancer drugs fail to have any effect in the body. Recently the X-ray structure of P-gp was resolved (Aller et al, 2009). We have built a 3-D physical model based on this X-ray structure which highlights the hydrophobic and hydrophilic regions of the protein, nucleotide binding domains, and active site residues that are important for verapamil, a common heart medication, binding. As it has not yet been possible to identify whether a drug is or is not a substrate of P-glycoprotein, this 3-D model may lend insight into this prediction.
Our ModelOur Model
In our model of P-glycoprotein, the hydrophilic regions are highlighted in magenta, the hydrophobic regions are highlighted in violet, the active site residues for the drug Verapamil* is highlighted in green, and the Nucleotide Binding Domains or NBDs are highlighted in yellow. Since P-glycoprotein is a dimer, a molecule consisting of two similar subunits, only half of the dimer (or one of two subunits) is shown in 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 green. These residues are H60, A63, L64, S218, I302, L335, A338, F724, I864, G868, F938, T941, L971, V978, G980, and A981. The Nucleotide Binding Domains (NBDs), which are highlighted in yellow, 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.
- For more information about Verapamil, please refer to ‘Medical Implications of P-glycoprotein.’
-- The flaps are not shown because they are too fragile to crystallize.