An Anglo-US team of researchers has unveiled the first structure of a membrane transport protein, a class of molecules whose primary job is to move elements as diverse as nutrients and neurotransmitters across cell membranes.
MTPs are targeted by a number of top-selling drugs, including Eli Lilly's antidepressant Prozac (fluoxetine) and AstraZeneca's ulcer treatment Losec (omeprazole). Disruptions in their functioning are thought to be involved in a number of diseases, including depression, stroke and diabetes, and knowledge of the structure of one member of the family will help drive understanding of other types.
The scientists, from Imperial College London in the UK and the USA's University of California, Los Angeles, report in Science that they have solved the three-dimensional structure of the bacterial membrane transport protein lactose permease (LacY), the most studied member of the so-called 'major facilitator superfamily' of MTPs. The molecule uses an electrochemical proton gradient to provide the energy to drive transport of lactose across the cell membrane.
The researchers, headed by UCLA's Ronald Kaback and sponsored by the Howard Hughes Medical Institute in the USA, produced a crystal version of LacY after nearly 12 years' work in which they had been continually frustrated by LacY's unstable structure. The discovery of a more-stable mutant form of the protein provided the breakthrough in producing a crystalline form of the MTP, and the three-dimensional structure was elucidated using X-ray crystallography.
According to Kaback, solving the structure of LacY is an achievement that will likely have important implications for a broad range of studies of membrane transport proteins. "The most important thing about this structure is that we've shown it can be done, because people have shied away from attempting to structure these proteins for a long time," he said.
"I think that this represents an important paradigm shift in the field, because these are incredibly important proteins," continued Kaback. He pointed out that 30 per cent of the genome encodes membrane proteins, most of which are transport proteins, and predicted that "20 years from now every soluble protein that can be crystallised is going to be crystallised."