Liz Carpenter
Professor of Protein Structural Biology
Membrane proteins are the gateways to the cell. All cells and organelles are surrounded by an oily, impermeable lipid bilayer and many small molecules can only cross this barrier by passing through protein molecules embedded in the bilayer. Many nutrients, ions, waste products and even DNA and proteins enter and leave cells only via proteins which are tightly controlled, thus maintaining the integrity of the cell. Communication between cells is also mediated by these proteins often by binding signaling molecules outside cells and amplifying the signal by triggering chemical reactions inside the cell. These diverse functions are fulfilled by a huge variety of membrane proteins, in fact approximately 15% of all the genes in the human genome code for these proteins. Given their location on the surfaces of cells, it is not surprising that membrane proteins are often found to be the targets for drugs, such as the calcium channel blockers used to treat heart disease and potassium channel blockers which are used in diabetes treatment. Indeed membrane proteins are involved in the development of many diseases, including heart disease, cancer, cystic fibrosis, Alzheimer’s, Parkinson’s and other neurological diseases, kidney disease and epilepsy.
My group at the structural Genomics Consortium in Oxford aims to solve the three dimensional structures of human membrane proteins using X-ray crystallography. We purify proteins, pursuad them to form crystals, and then expose them to a beam of X-rays. The resulting diffraction patterns can then be used to understand the positions of all the atoms in the protein. We then study the structures in complex with inhibitors and drugs, using this information to improve and extend the available treatments for disease. There are less than 50 structures of human membrane proteins known and we therefore seak to develop methods to make this process more efficient. In the past four years we have established a working high-throughput system for the producing human membrane proteins for structural studies.
The IMP group at the SGC studies proteins from a variety membrane protein families, including ion channels enzymes and ABC transporters. To date we have solved structures of of proteins in three different areas:
- We solved the first structure of a human ABC transporter, ABCB10, a mitochondrial protein which is important for heme production and for resistance of mitochondria to oxidative stress.
- Premature ageing syndromes can be caused by a failure in the processing of the lamin proteins, which form a network of fibres underlying the nuclear membrane within cells. We have solved the structure of a zinc metalloprotease, ZMPSTE24, which is responsible for two steps in this processing. This structure has allowed us to see how mutations in the ZMPSTE24 protein can lead to premature ageing diseases, which provide a model for normal ageing.
- Recently we have solved and deposited the structure of a human ion channel, TREK-2, one of the family of K2P proteins which are responsible for the background leak current that helps to maintain the membrane potential and also are susceptible to a range of physiological and pharmacological stimuli.
Recent publications
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A lower X-gate in TASK channels traps inhibitors within the vestibule
Journal article
Rödström KEJ. et al, (2020), Nature, 582, 443 - 447
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Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2.
Journal article
Wang Q. et al, (2020), Structure (London, England : 1993), 28, 169 - 184.e5
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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
Journal article
Bushell SR. et al, (2019), Nature Communications, 10
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Cryo-EM structures of the human glutamine transporter SLC1A5 (ASCT2) in the outward-facing conformation.
Journal article
Yu X. et al, (2019), eLife, 8
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A pharmacological master key mechanism that unlocks the selectivity filter gate in K
+
channels
Journal article
Schewe M. et al, (2019), Science, 363, 875 - 880