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Posted: April 23, 2010

Transporter protein study delivers a world first

(Nanowerk News) A team of EU-funded researchers has become the first in the world to work out the structure of a transporter protein in all three main structural states. Transporter proteins are responsible for ferrying substances into and out of cells and the new findings, published in the journal Science, could lead to new drugs for a range of diseases and disorders.
EU support for the work came from the E-MEP ('European membrane protein') project, which is financed under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6) and the EDICT ('European drug initiative on channels and transporters') project, which is funded through the Health Theme of the Seventh Framework Programme (FP7).
Transporter proteins carry molecules across cell membranes by switching between three different states. The first state is characterised by an outward-facing cavity. A compound enters this cavity and latches on to a binding site; the protein then shifts to a second, 'occluded' state, in which the cargo is locked inside the protein. Finally, the transporter undergoes another shape change, opening up a cavity on the inside of the cell. The system works like a kissing gate, i.e. the cavity is open or one side or the other but there is never a direct channel through the protein.
There are thousands of transporter proteins in the body, and studying them is extremely challenging. As they break down in water, it is very hard to purify and crystallise them, and even if high quality crystals are produced, working out their structure requires many months of work. Until now, no-one has succeeded in elucidating all three structural states for a single protein, and so ideas about how the system as a whole works have been based on findings from different proteins.
'Previous models gave us a broad understanding of the mechanism involved, but this could never really be usefully applied for drug development,' commented Professor Peter Henderson of the University of Leeds in the UK. 'The goal for researchers in this area has always been to observe the entire mechanism in a single protein.'
This study, which involved scientists from Japan and the UK, focused on Mhp1 (Microbacterium hydantoin permease 1) - the transporter protein responsible for transporting molecules called hydantoins into cells, where they are converted into amino acids, the building blocks of proteins. Faults in Mhp1 and related transporter proteins have been linked to a number of diseases including neurological and kidney conditions and cancer.
The team published details of Mhp1's outward-facing and occluded structures in the journal Science back in 2008. This latest paper explains Mhp1's inward-facing structure. The findings provide new insights into how the protein switches between the three states.
'This third structure completes the picture and we can now understand Mhp1's 'alternating access' mechanism in great detail,' explained Dr Alexander Cameron from the Division of Molecular Biosciences at Imperial College London, UK. '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 hope is that understanding transporter proteins' mechanisms will help researchers use them to ferry drugs into cells.
Scientists from the EDICT project are already drawing on the revelations concerning Mhp1's mechanism. 'We've found around 20 compounds that match Mhp1's binding site, and of these, 3 have been shown to bind. I think we are entering an exciting period of discovery,' stated Professor Henderson, who is also the EDICT project coordinator.
Meanwhile, the researchers are planning to investigate precisely what triggers the protein to change from one state to another.
'It's taken a long time to get to this point - over 10 years - but then difficult science takes time. This is the point at which blue skies research evolves into useful applications,' said Professor Henderson. 'It's been the best thing I've been involved in during my academic career.'
Source: Cordis
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