Finding the Crystal Structure of P-gp: A
Protein that Makes Cancer Cells Resistant to Chemotherapy
summary written by Raven Hanna
Medications can be rendered ineffective through cells developing multidrug resistance. This is the case in many forms of cancer cells that fail to respond to chemotherapy. The ability of these cells to avoid the effects of drugs can be due to the actions of P-glycoprotein (P-gp). This protein sits in the membranes of cells and acts like a pump. It ushers a wide range of potentially harmful molecules from inside the membrane to outside the cell. Unfortunately, it can also mediate the removal of life-saving medications.
The mechanism behind the ability of P-gp to act upon such a diverse range of chemicals has been a mystery. The recent crystal structure of P-gp sheds light on its mechanism and brings scientists a step closer to developing ways to prevent P-gp from banishing medicines from cells.
A research team led by Prof. Geoffrey Chang of The Scripps Research Institute used SSRL Beam Lines 9-2 and 11-1 to collect part of the x-ray diffraction data used to solve the structure of mouse P-gp. In the crystal, the protein looks like a "V" with bulbous ends. The scientists believe that they caught P-gp in the pre-transport state, where the protein is ready to bind a target molecule. The open arms of the "V" extend through the membrane into the cytoplasm and the closed point of the "V" extends outside the cell.
P-gp likely works by binding a molecule in a central cavity and closing its open arms to create a cage. It then opens the other ends of the arms to reverse the "V", depositing the trapped molecule outside the cell. While both the bacterial and the mouse versions of the molecule have many hydrophobic side-chains lining their cavities, the mouse P-gp has many more aromatics. These sticky residues could bind to a variety of organic molecules, which may explain P-gp's ability to target a wide range of molecules.
Understanding how medicinal molecules bind to P-gp will enable researchers to redesign existing drugs to avoid falling into this trap and thus be more likely to retain their potency. This work was published in the March 27 issue of the journal Science.
Stephen G. Aller, Jodie Yu, Andrew Ward, Yue Weng, Srinivas Chittaboina, Rupeng Zhuo, Patina M. Harrell, Yenphuong T. Trinh, Qinghai Zhang, Ina L. Urbatsch, Geoffrey Chang (2009) Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science, 323, 1718-1722.