A study published this week in the journal Proceedings of the National Academy of Sciences USA (PNAS) has revealed the first structure of one of the eight HATs (heteromeric amino acid transporters). Achieved through collaboration between biochemists at Institute for Research in Biomedicine (IRB), experts in electronic microscopy at the University of Bern, and computational biologists in the Joint IRB-BSC Programme, this breakthrough paves the way for further research into the functions of the other seven HATs and the resolution of their structures. Moreover, this study provides the first sufficiently detailed structural data to tackle their inhibition through drugs.

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HATs are, as the name implies, amino acid transporters, and they exert their action in the cell membrane. Because of their nature, they are extremely difficult to crystallize and consequently no structural data are available for these molecules at the atomic level. However, for rational drug design this information is imperative. In humans, there are eight HAT molecules. These are associated, for example, with the following: rare diseases called aminoacidurias, such as lysinuric protein intolerance and cystinuria; the development of infections caused by the Kaposi sarcoma virus; various types of cancer; and relapse in cocaine use.

The study published this week in the PNAS (doi:10.1038/nbt.2831) includes among the first authors the post-doctoral researcher Albert Rosell and the PhD student Elena Álvarez-Marimon from the Heterogenic and Multigenic Diseases Laboratory at the IRB Barcelona, led by Manuel Palacín, a world expert in heteromeric amino acid transporters.

Manuel Palacín’s basic research into HATs seeks to identify new therapeutic targets and to improve diagnostic tools for all conditions that involve HATs, with a special focus on aminoacidurias. “HATs are mini machines that are inserted into the membrane and are in constant movement, engulfing amino acids from the extracellular space and releasing them in the cytoplasm or vice-versa,” explains Palacín. “We knew the structure of one of the parts. Now, for the first time, we have the low resolution of the entire complex,” he says.

The study started as part of the European project EDICT (European Drug Initiative on Channels and Transporters), a consortium comprising 21 groups and funded by 11 million euros, which aims to increase the database of membrane protein structures. In 2008, at the beginning of the project, about 100 membrane protein structures were known. Today, this number has tripled, Palacín’s group having contributed two of these new structures.

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