Summary

So you have reached the end of our blog and here are the key points which should not be forgotten!

It was neccessary for Krishnamurthy and Gouaux to search for new crystal structures of LeuT intermediates because without them our understanding of NSSs would be hindered.

2 conformations were crystallised and their structures determined.

This led to a greater understanding of the mechanism by which LeuT takes up a neurotransmitter and releases it inside the cell.

What is the wider impact of this research?

As already mentioned, LeuT has great clinical relevance. Many therapeutic drugs which have been developed to target and inhibit NSSs have been tested on LeuT so understanding the mechanism by which it works in more detail could lead to more effective drug design. Examples which block NSS action include diuretics, anticonvulsants and antidepressants. As this research has demonstrated a more detailed mechanism by which molecules are transported, there is potential for new drugs which could target previously unknown aspects of the mechanism. Furthermore, existing drugs may be enhanced because what they inhibit may be more precisely known. It is also fair to bring up the importance of LeuT to study the impact of recreational drugs as it is known that they also inhibit uptake of neurotransmitters.

References

H. Krishnamurthy and E. Gouaux (2012) X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature 481, 469-474.

Z. Zhou, J. Zhen, N. K. Karpowich, R. M. Goetz, C. J. Law, M. E. A. Reith and D.-N. Wang (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317, 1390-1393.

S. K. Singh, A. Yamashita and E. Gouaux (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.

S. K. Singh (2008) LeuT. Channels 2, 380-389.

C. L. Piscitelli, H. Krishnamurthy and E. Gouaux (2010) Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature 468, 1129-1132.