Structure and Mechanism of Solute Carrier (SLC) Transporters
SLC transporters are the targets for many therapeutics and they often play a major role in drug pharmacokinetics. Understanding the mechanisms by which SLC transporters shuttle and move ions, drugs, and natural compounds across membranes is of fundamental importance. Because of the technical difficulties in working with membrane proteins our mechanistic understanding is very limited. The Drew lab aims to understand the biophysical and chemical principles governing transporter function.
Solute transporters have to scan the cells surface to absorb only specific molecules out of all of the tens of millions of molecules they encounter. The Drew lab determined the first X-ray structures of a glucose (GLUT) transporter with doors open to both the outside and the inside of the cell. Drew has proposed a glucose transport mechanism and this model has been further refined by structures of a related malarial parasite sugar transporter with doors closed to both sides. GLUT transporters are responsible for maintaining blood glucose homeostasis in humans, and this work provides a foundation for their selective pharmacological control to combat human diseases, such as cancer and diabetes. His lab has further investigated how salt (sodium) is absorbed and exchanged for protons across cell membranes to control the cell’s internal pH by determining the first cryo-EM structures of mammalian Na+/H+ exchangers. These proteins operate very differently to the sugar transporters, and this work has aided in the general acceptance of an “elevator” transport mechanism, as first described in glutamate transporters.
The Drew lab will continue to combine cryo EM structures with biophysical and biochemical assays to deepen the mechanistic models for sugar and ion transport, and to establish how the activity of these proteins are regulated by interaction with other proteins and lipids. These goals are facilitated by the development of novel methods to aid in the functional and structural investigation of SLC transporters.
Knut och Alice Wallenberg, VR, ERC, Cancerfonden, Göran Gustafsson Foundation
Membrane Proteins, Transporters, Structure, Mechanism, Drug interactions, Biotechnology, Biophysics
Pascal Meier, cryo EM and ion transporters
Sarah McComas, MD simulations and sugar transporters
Surabhi Koltrane, cryo EM and ion transporters
Sukkyeong Jung, cryo EM and ion transporters
Ashutosh Gulati, X-ray, cryo EM and ion transporters
Hyunku Yeo, cryo EM and ion transporters
Dohwan Ahn, X-ray, NMR and sugar transporters
Claudia Alleva, MD simulations and sugar transporters
Marta Bonaccorsi, NMR and MD simulations of sugar transporters
Rachel North, cryo EM and sugar transporters
Tom Reichenbach, cryo EM and sugar transporters
Albert Suades, biochemical assays and sugar transporters
Ved Mehta, cryo EM and ion transporters
Magnus Claesson, X-ray and sugar transporters