(cm) A fundamental property of living organisms and their cells is the exchange of material with their surroundings. Consequently, there are various systems that ensure this exchange. They include the ABC (ATP-Binding Cassette) transporters. These are well-known because, among other things, they contribute to the resistance of cancer cells and bacteria by transporting medicines or antibiotics back out of cells again.

In spite of their far-reaching importance, up to now not enough was known about their fine structure and the transport mechanism. ETH researchers Roger J.P. Dawson and Kaspar P. Locher from the Institute for Molecular Biology and Biophysics have now succeeded in revealing the structure of SAV1866, an ABC transporter of the bacterium Staphylococcus aureus, with a resolution of 3 Angstroms (1). The paper, which also helps to provide a better understanding of the transport mechanism, was published this Wednesday (30.08.06) as an Advance Online Publication in the specialist journal “Nature” (2). It is part of the NCCR (National Center of Competence in Research) Structural Biology, a Priority Program of the Swiss National Science Foundation (3).

The researchers crystallised SAV1866 in the presence of the molecule ADP and determined the electron density of the transporter by using X-ray crystallographic methods and the X06SA beam line of the synchrotron Swiss Light Source at the Paul Scherrer Institute. Although ADP had been added, because of the crystallisation conditions that were used, the scientists obtained the state of the transporter as though it was binding ATP, the basic energy unit of the cell. Thus the structural model of SAV1866 corresponds to a state with regard to the cell in which it is open to the exterior.

In the case of the ABC transporter, which is built of two identical polypeptide chains, the extremely complicated interlocking of the two halves was apparent. The region that spans through the membrane is twisted upon itself and forms two wings consisting of mutually embracing parts of the two sub-units. The junction between the region spanning through the membrane and the protein region in the cell interior turns out to be similarly intermeshed. However, this is not the only place where this close interaction exists. The two sites at which ATP is cleaved are also formed by a common interface of the proteins.

Detailed illustration of an ABC transporter. The structure of SAV1866 reveals the two wings penetrating through the membrane (grey region) and the transporter section with bound ATP in the interior. (Photo: R. Dawson) large

All in all, the data on SAV1866 published in the study define the architecture of a bacterial ABC ‘multi-drug’ transporter in the state in which it is open to the exterior, and bring this in line with the existing data of comparable bacterial and human ABC export systems. It explains shared mechanistic features involved in the transportation of the widest variety of pharmaceutically relevant substances out of the cell. Since no high-resolution structures of medicinally relevant ABC transporters exist, Sav1866 could prove to be a valuable structural model that might be usable, for example, to develop cancer drugs. Future research is aimed at gaining further insights into the transport mechanism and at describing an ABC transporter in the state in which it is open to the interior relative to the cell.