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On Nobel Prizes and Membranes Proteins

What makes this a special prize for ITQB

Oeiras, 22.10.12

This year’s Nobel Prize for Chemistry was awarded to Robert J. Lefkowitz and Brian K. Kobilka "for studies of G-protein-coupled receptors". In more ways than one, this prize has a special meaning for ITQB. Not only because of the related ongoing research at ITQB but also because of the involvement of an ITQB alumnus in Koblika’s research.

Cell receptors are crucial for cells to sense their environment and in this particular family we find receptors for adrenalin, dopamine, serotonin, light, flavour and odour. The importance of G-protein coupled receptors is such that they are targets of 50 % of the available medicines. But what makes this work so extraordinary is how difficult G-protein coupled receptors have been to study.

As Margarida Archer, head of the Membrane Protein Crystallography Lab explains, part of the difficulty in studying these proteins stems from the fact that G-protein receptors are membrane proteins and are thus extremely difficult to isolate and purify, let alone crystallize for structural studies. But determining the 3D structure of proteins is essential to fully understand its mechanism of action. In fact, the Swedish Academy has already rewarded with Chemistry Nobel Prizes many structural works, including some on other membrane proteins (electron-transport proteins in 1988, ion channels in 2003). Brian K. Kobilka and his team succeeded in obtaining an image of the G-protein-coupled receptor, something many scientists thought unattainable.

“A crowning achievement” is how the Nobel Academy labeled the revelation by Kobilka and his coworkers of the three-dimensional structure of a fully functional G-coupled receptor. The work, co-authored by ITQB alumnus David Aragão, was published in Nature in 2011.

There are essentially two methods available to crystallize membrane proteins: using detergents that mimic the membrane and essentially solubilise the protein or resorting to lipidic mesophases. This technique involves making an artificial lipid bilayer to incorporate the protein of interest and was successfully applied for Koblika’s protein receptors in Martin Caffrey’s lab in Ireland, where  David Aragão was working at the time. “I left my work to work on this project” David explains in a recent interview, “We did the crystallization and then flew to the US to collect data in Chicago’ synchrotron”. Having had the opportunity to contribute to this work expectedly makes David very proud. David Aragão, now in Melbourne, graduated at ITQB in 2007 under the supervision of Carlos Frazão.

The considerable interest membrane proteins have for the pharmaceutical industry and that fact than only 1% of the known structures correspond to membrane proteins, makes these extremely attractive, albeit difficult, research models. At ITQB, the Membrane Protein Crystallography Lab is now working on several of these proteins including membrane transporters and bacterial sensor kinases associated with antibiotic resistance.

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