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PERSPECTIVES IN PHARMACOLOGY

Structures and Models of Transporter Proteins

Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway

Transporter proteins in biological membranes may be divided into channels and carriers. Channels function as selective pores that open in response to a chemical or electrophysiological stimulus, allowing movement of a solute down an electrochemical gradient. Active carrier proteins use an energy producing process to translocate a substrate against a concentration gradient. Secondary active transporters use the movement of a solute down a concentration gradient to drive the translocation of another substrate across a membrane. ATP-binding cassette (ABC) transporters couple hydrolysis of adenosine triphosphate (ATP) to the translocation of various substrates across cell membranes. High-resolution three-dimensional structures have now been reported from X-ray crystallographic studies of six different transporters, including two ATP-binding cassette (ABC) transporters. These structures have explained the results from many previous biochemical and biological studies and shed new light on their functional mechanisms. All these transporters have -helical structures of the membrane-spanning domains, as suggested from many previous studies, and some of the helices have irregular shapes with kinks and bends. Together these crystal structures demonstrate the large flexibility of transporter proteins and that substantial movements take place during the substrate translocation process, which to a certain extent may distinguish active carriers from channel proteins. These structures and other low-resolution structures of membrane proteins have served as a basis for construction of three-dimensional protein models that have provided insight into functional mechanisms and molecular structures and enabled formulation of new hypotheses regarding transporter structure and function, which may be experimentally validated.

Address correspondence to: Dr. Svein G. Dahl, Department of Pharmacology, I.M.B., University of Tromsø, N-9037 Tromsø, Norway. E-mail: sgd{at}fagmed.uit.no

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