Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters.

MedicalResearch.com eInterview with Christian Löw, Ph.D.
Department of Medical Biochemistry and Biophysics
Karolinska Institutet
SE-171 77 Stockholm Sweden

MedicalResearch.com: What are the main findings of the study?

Dr. Löw: In order to grow, cells need fuels such as sugars. Specialized proteins that reside in the cell envelope transport these nutrients into the cell; XylE is a bacterial transport protein that is highly similar to members of the human GLUT transporters. Our study describes for the first time the mechanistic details of how cells import sugars by resolving the different steps of the transport cycle at almost atomic resolution. Tumors are especially dependent on the uptake of sugars and other nutrients via these transporter systems in order to be able to grow rapidly. A possible strategy for cancer treatment therefore would be to block these transporters in the cell membrane, thus starving out and killing the cancer cells. Our structures can be used for initial structure based drug design studies to develop efficient and specific inhibitors against members of the GLUT family. We believe that our detailed mechanistic insights could become the basis for new strategies to fight cancer cells.

Specialized proteins that reside in the cell envelope transport these nutrients into the cell; XylE is a bacterial transport protein that is highly similar to members of the human GLUT transporters
MedicalResearch.com: Were any of the findings unexpected?

Dr. Löw: When determining the structures of the transporter under different conditions we realized that it was trapped in different conformations representing snapshots of the protein along the reaction cycle. This was at first unexpected, a serendipity finding!

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Löw: Our study provides a solid basis for understanding the molecular mechanism of these transport proteins. This opens up opportunities to develop more rapidly and more efficiently new substances that may inhibit GLUT transporters. Such GLUT inhibitors could potentially be used to treat cancer in the future.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Löw:We have obtained detailed structural information of the transporter in three conformational different states. To extend our knowledge on the transport mechanism we aim to stabilize and characterize the protein at its initial state of the reaction cycle, namely a fully outward open conformation. We believe that the bacterial XylE transporter represents a perfect model system for nutrient uptake systems since many of them are supposed to share a common mechanism.

Citation:

Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters.

Quistgaard EM, Löw C, Moberg P, Trésaugues L, Nordlund P.

1] Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. [2].
Nat Struct Mol Biol. 2013 Apr 28. doi: 10.1038/nsmb.2569.
[Epub ahead of print]