Flip-side of MsbA Transporter

Membrane-bound transporter proteins have emerged as a key defense mechanism against potential toxins. The ATP-binding cassette (ABC) transporters belong to the largest known transporter gene family and translocate a variety of substrates including chemotherapy agents. Furthermore, the expression of the ABC multidrug transporters has been implicated in tumor cell resistance to anticancer therapy and the altered disposition (and associated toxicity) of chemotherapy drugs. In both humans and bacteria, ABC transporters have been implicated in antibiotic and cancer drug resistance. Therefore, ABC transporters represent key targets for the development of multidrug resistance reversal agents

Using x-ray diffraction data collected at SSRL Beam Line 11-1 and at the ALS, researchers Geoffrey Chang and Christopher Reyes from The Scripps Research Institute have determined the 4.2 Å x-ray crystal structure of MsbA in complex with the transition state mimic ADP, vanadate (an analog of the g phosphate of ATP) and the human immunomodulatory substrate Ra lipopolysaccharide. Together with other MsbA structures, the current structure provides a framework for interpreting functional data concerning multidrug resistant ABC transporters. The structure supports a model involving a rigid-body troque of the two transmembrane domains during ATP hydrolysis and suggests a mechanism by which the nucleotide binding domain communicates with the transmembrane domain.