Elucidating Crystal Structures of an ABC Multidrug Transporter That obstacle with Cancer Chemotherapy
- Release Date
- 04 Mar, 2014
- BL41XU (Structural Biology I)
Kyoto University
Topic
• CmABCB1 of which structure and functions are homologous to those of P-glycoprotein*1 (a human ABC multidrug efflux transporter) was found in a eukaryotic organism living in hot springs for the first time.
• The atomic-resolution structure of CmABCB1 was determined by X-ray crystallography.
• A unique inhibitor preventing action of CmABCB1 was discovered and its inhibition mechanism was elucidated.
• The mechanism by which CmABCB1 actively effluxes a wide variety of compounds was revealed at the atomic level.
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A research group led by Hiroaki Kato(professor, concurrently serving as a visiting researcher at RIKEN) of the Graduate School of Pharmaceutical Sciences, Kazumitsu Ueda (professor) of the Institute for Integrated Cell-Material Sciences (iCeMS) and Jun Hiratake (professor) of the Institute for Chemical Research, Kyoto University (Hiroshi Matsumoto, President), and Professor Hiroaki Suga (professor) of the Graduate School of Science, the University of Tokyo, found a membrane protein, CmABCB1, in a eukaryotic organism living in hot springs. CmABCB1 has the structure and functions very similar to those of adenosine triphosphate (ATP)-binding cassette (ABC) multidrug transporters that disturb cancer chemotherapy. The research group also succeeded in solving the molecular structure and multidrug efflux mechanism of CmABCB1. The cancer cells remaining after the first anticancer drug therapy acquire resistance to various anticancer drugs by expressing a number of ABC multidrug efflux transporters, which becomes an obstacle to cancer chemotherapy. By X-ray crystallography, the researchers determined the molecular structure of CmABCB1 in detail and clarified the mechanism by which it excretes a wide variety of molecules with various chemical structures. Their achievements were published online in the American scientific journal Proceedings of the National Academy of Sciences on 3 March 2014 prior to publication in the printed version (Vol. 111, No. 11, 4049-4054). |
<<Figures>>
The two subunits of CmABCB1 act as a pair. One subunit is colored, whereas the other is shown in gray. The six cylindrical structures (α helices TM1‒TM6) composing the TMD of the colored subunit are numbered from 1 to 6. α Helices are shown as ribbons. An inhibitor aCAP (yellow and black) is bound to TM2 (blue-green and gray) near the boundary between the extracellular side and the cell membrane. The cell membrane that consists of a bilayer of phospholipids is also shown in the models.
Because hydrophobic*2compounds that easily pass through a cell membrane are slightly soluble in cytoplasm, they are temporarily pooled at the boundary between the cell membrane and the cytoplasm when they enter the cell from the outside. CmABCB1 transports the compounds into an inner cavity through a size-variable gate. CmABCB1 seems to transport any hydrophobic compounds regardless of their chemical structure because the ceiling of the cavity easily adsorbs hydrophobic compounds. When the compounds near the ceiling come into contact with the switch, the gates on the ceiling (TM1 and TM6) open to excrete the compounds from the cell. The power required to open and close the gates on the ceiling and the cytosolic side are supplied by the motion of the ATP engine (NBD)*3 .
<<Glossary>>
*1 P-glycoprotein
A phenomenon in which substances are separated into two phases. In this research, phase separation indicates a state in which two or more types of metals exist separately without being mixed with each other at the atomic level.
*2 Hydrophobic and hydrophilic
A type of electron microscopy in which a finely focused electron beam is scanned over a sample and the transmission electrons scattered at high angles are detected using an annular detector.
*3 NBD
Percentage of reactants that are consumed in the reaction.
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