A team of academic researchers in the UK has fitted the last piece of a jigsaw that provides a “remarkable insight” into how essential chemicals move into body cells, opening up new avenues for drug development.

The research published in Science involves mapping the inward-facing structure of the bacterial Mhp1 transporter protein. This is one of three distinct structural states, controlled by ion gradients, that occur when transporter proteins carry molecules through a cell membrane.

It is the first time the entire mechanism has been observed in a single protein, note the researchers from the University of Leeds, Imperial College London and Oxford University, who say that scientists have been looking for 25 years to capture the 3D atomic models of a single transporter protein in each of its three main structural states.

“Previous models gave us a broad understanding of the mechanism involved, but this could never really be usefully applied for drug development,” observed Peter Henderson, Professor of Biochemistry and Molecular Biology at the Astbury Centre for Structural Molecular Biology, University of Leeds.

Professor Henderson also co-ordinates the European Drug Initiative for Transporters and Channels (EDICT), which has already found around 20 compounds that match the binding site of the Mhp1 protein. Three of these compounds have been shown to bind to the protein.

Detailed knowledge of Mhp1’s ‘alternating access’ mechanism could “unlock new drug developments in several ways”, Professor Henderson suggests. “Altering the delivery of compounds into a cell is one potential benefit for treating illness.” This could be useful, for example, in treating conditions where certain chemicals need boosting permanently, such as serotonin in depression and glucose in diabetes.

Three states

The first state involved in the transport of molecules through otherwise impermeable cell membranes comprises an outward-facing cavity, the researchers explain. A compound will enter this cavity and attach to a binding site, at which point the protein will move to a second state with its cargo locked inside. The third state occurs when the protein opens up a cavity on the inward-facing side to release the compound into the cell.

The UK research team has been studying the Mhp1 transporter protein for more than ten years. The scientists’ observations of the first two structures were published in Science in October 2008. The Mhp1 protein transports molecules known as hydantoins into cells, where they are converted into useful amino acids.

Mhp1 was produced at the University of Leeds, where the protein’s function was originally discovered in 2000. The structures were determined by X-ray crystallography and analysed at Imperial College London and the Imperial College Membrane Protein Laboratory (MPL). To investigate further the transitions between the three states of the protein, dynamic molecular simulations were carried out at Oxford University.

“This third structure completes the picture and we can now understand Mhp1’s ‘alternating access’ mechanism in great detail,” commented Dr Alexander Cameron from the Division of Molecular Biosciences at Imperial College London.

“We also unexpectedly found that the structures are similar across many transporter proteins previously thought to be different, so we’re expecting our model to help achieve some rapid progress in the research of colleagues around the world.”

The research team consists of Professor Henderson and colleagues from Leeds, who expressed and purified the Mhp1 protein; Professor So Iwata, Dr Alex Cameron and colleagues from Imperial College London and the MPL, who imaged the crystals and combined all the information to propose a mechanism for the alternating access model; and Professor Mark Sansom and Dr Oliver Beckstein from the University of Oxford, who authenticated the plausibility of the transitions between the three states.

The team was funded by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), the Wellcome Trust, the European Union and the Japanese Science and Technology Agency.