Understanding the three-dimensional structure of molecular machines within our cells is critical for determining how they function normally and go awry in disease states, unlocking potential new routes for treatment. Our lab solves atomic resolution structures, and places them in their cellular context, using multiscale cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) techniques. We combine this with in vitro reconstitution, cell biology, and live fluorescence imaging to dissect molecular mechanisms underlying function.
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We use multi-scale electron microscopy to address biomedical questions.
Complementary techniques in the lab to dissect molecular mechanisms from different angles.
A core focus of our lab is using cutting-edge structural biology approaches to understand the workings of molecular machines from atomic to cellular scales. At the atomic scale, we use single particle cryo-EM and take advantage of recent advances in AI-assisted image processing to uncover the conformational changes that molecular machines undergo during their functional cycles. We work with clinicians to dissect effects of novel disease mutations on these cycles. We gain insight into the cellular context and regulation of these machines using in situ cryo-ET and focussed ion beams to slice windows into cellular compartments that would otherwise be too thick for imaging. We test hypotheses from these structural biology approaches using in vitro reconstitution, biochemical techniques, and live fluorescence microscopy experiments to quantify dynamics of function. A current target in the lab is the dynein-2 motor protein that powers transport within essential signalling antennae called cilia. Together our multidisciplinary approaches enable us to dissect molecular mechanisms of proteins and pathogens central to human health.
We collaborate with the Roberts lab, offering many joint projects, and sharing lab meetings, ideas, and a contiguous lab space.
2022
IFT-A Structure Reveals Carriages for Membrane Protein Transport into Cilia.
Hesketh, S.J., Mukhopadhyay, A.G., Nakamura, D., Toropova, K. and Roberts, A.J.
Cell – 185(26): 4971-4985
2020
DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.
Vig, A., Poulter, J.A., Ottaviani, D., Tavares, E., Toropova, K, Tracewska, A.M., Mollica, A., Kang, J., Kehelwathugoda, O., Paton, T., Maynes, J.T., Wheway, G., Arno, G., Genomics England Research Consortium; Khan, K.N., McKibbin, M., Toomes, C., Ali, M., Di Scipio, M., Li, S., Ellingford, J., Black, G., Webster, A., Rydzanicz, M., Stawiński, P., Płoski, R., Vincent, A., Cheetham, M.E., Inglehearn, C.F., Roberts, A., Heon, E.
Genet Med. – 22(12):2041-2051.
2019
Structure of the Dynein-2 Complex and its Assembly with Intraflagellar Transport Trains.
Toropova, K., Zalyte, R., Mukhopadhyay, A.G., Mladenov, M., Carter, A.P. and Roberts, A.J.
Nature Structural & Molecular Biology – 26(9): 823-829
2017
Intraflagellar Transport Dynein is Autoinhibited by Trapping of its Mechanical and Track-binding Elements.
Toropova, K., Zalyte, R., Mukhopadhyay, A.G., Mladenov, M., Carter, A.P. and Roberts, A.J.
Nature Structural & Molecular Biology – 24(5): 461-468.
2017
Capsids and Genomes of Jumbo-Sized Bacteriophages Reveal the Evolutionary Reach of the HK97 Fold.
Hua, J., Huet, A, Lopez, C.A., Toropova, K., Pope, W.H., Duda, R.L., Hendrix, R.W., Conway, J.F.
mBio – 8(5):e01579-17.
2014
Lis1 regulates dynein by sterically blocking its mechanochemical cycle.
Toropova, K., Zou. S., Roberts, A.J., Redwine, W.B., Goodman, B.S., Reck-Peterson, S.L., Leschziner, A.E.
eLife – 7:3:e03372.
2011
The herpes simplex virus 1 UL17 protein is the second constituent of the capsid vertex-specific component required for DNA packaging and retention.
Toropova, K., Huffman, J.B., Homa, F.L., Conway, J.F.
J. Virol. – 85(15):7513-22.
2011
Visualising a viral RNA genome poised for release from its receptor complex.
Toropova, K., Stockley, P.G., Ranson, N.A.
J Mol Biol. – 408(3):408-19.