Natively Inhibited Trypanosoma brucei Cathepsin B Structure Determined by Using an X-ray Laser
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Diffraction Before Destruction: A bottleneck in x-ray crystallography is the growth of well-ordered crystals large enough to obtain high-resolution diffraction data within an exposure that limits radiation damage. Serial femtosecond crystallography promises to overcome these constraints by using short intense pulses that out-run radiation damage. A stream of crystals is flowed across the free-electron beam and for each pulse, diffraction data is recorded from a single crystal before it is destroyed. Redecke et al. (p. 227 , published online 29 November; see the Perspective by Helliwell ) used this technique to determine the structure of an enzyme from Trypanosoma brucei , the parasite that causes sleeping sickness, from micron-sized crystals grown within insect cells. The structure shows how this enzyme, which is involved in degradation of host proteins, is natively inhibited prior to activation, which could help in the development of parasite-specific inhibitors.
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A reasonably complete data set was obtained from a few hundred images using 148 crystals, in contrast to the tens of thousands to millions of crystals typically used in XFEL-based crystallography.
“Moreover, in contrast to the tens of thousands to millions of crystals typically used in XFEL-based crystallography experiments34, we obtained a reasonably complete data set from a few hundred images using 148 crystals (Methods).”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [34]
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Research works printed but not linked: 26
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- Authors
- Redecke, L., Nass, K., DePonte, D. P., White, T. A., Rehders, D., Barty, A., Stellato, F., Liang, M., Barends, T. R. M., Boutet, S., Williams, G. J., Messerschmidt, M., Seibert, M. M., Aquila, A., Arnlund, D., Bajt, S., Barth, T., Bogan, M. J., Caleman, C., Chao, T.-C., Doak, R. B., Fleckenstein, H., Frank, M., Fromme, R., Galli, L., Grotjohann, I., Hunter, M. S., Johansson, L. C., Kassemeyer, S., Katona, G., Kirian, R. A., Koopmann, R., Kupitz, C., Lomb, L., Martin, A. V., Mogk, S., Neutze, R., Shoeman, R. L., Steinbrener, J., Timneanu, N., Wang, D., Weierstall, U., Zatsepin, N. A., Spence, J. C. H., Fromme, P., Schlichting, I., Duszenko, M., Betzel, C., & Chapman, H. N.
- Affiliations
- Universität Hamburg (DE)
- Deutsches Elektronen-Synchrotron DESY (DE)
- SLAC National Accelerator Laboratory (US)
- University of Gothenburg (SE)
- University of Tübingen (DE)
- Arizona State University (US)
- Lawrence Livermore National Laboratory (US)
- Department of Cell and Molecular Biology, Uppsala University, Husargatan 3, SE-75124 Uppsala, Sweden.
- Corresponding author
- Redecke, Lars
- Nass, Karol
- Betzel, Christian
- Chapman, Henry N.
- ORCID
- Redecke, Lars
- Nass, Karol
- DePonte, Daniel P.
- White, Thomas A.
- Barty, Anton
- Stellato, Francesco
- Liang, Mengning
- Boutet, Sébastien
- Williams, Garth J.
- Messerschmidt, Marc
- Seibert, M. Marvin
- Aquila, Andrew
- Arnlund, David
- Bajt, Sasa
- Bogan, Michael J.
- Caleman, Carl
- Chao, Tzu-Chiao
- Fleckenstein, Holger
- Frank, Matthias
- Fromme, Raimund
- Hunter, Mark S.
- Johansson, Linda C.
- Katona, Gergely
- Kirian, Richard A.
- Koopmann, Rudolf
- Martin, Andrew V.
- Mogk, Stefan
- Neutze, Richard
- Shoeman, Robert L.
- Steinbrener, Jan
- Wang, Dingjie
- Weierstall, Uwe
- Zatsepin, Nadia A.
- Spence, John C. H.
- Fromme, Petra
- Schlichting, Ilme
- Duszenko, Michael
- Betzel, Christian
- Chapman, Henry N.
- Venue
- Science
- Published
- 2013-01-11
- Volume
- 339
- Issue
- 6116
- Pages
- 227-230
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3786669
- OpenAlex
- W2038009699
- Cited by
- 440
- References
- 0
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 13 · 2023: 6 · 2022: 14 · 2021: 17 · 2020: 26 · 2019: 44 · 2018: 30 · 2017: 36 · 2016: 55 · 2015: 67 · 2014: 78 · 2013: 38 · 2012: 1
- FWCI
- 27.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- Figshare (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- European XFEL (submittedVersion)
- Funders
- National Institutes of Health (1R01GM095583)
- Office of Basic Energy Sciences
- U.S. Department of Education (DE-AC52-07NA27344)
- National Science Foundation (MCB-1021557, MCB-1120997)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- Trypanosoma brucei, cathepsin B, cysteine protease, sleeping sickness, serial femtosecond crystallography, X-ray free-electron laser, microcrystals, protein structure, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Cathepsin B, Crystallization, Enzyme Precursors, Glycosylation, Models, Molecular, Molecular Sequence Data, Protein Conformation, Trypanosoma brucei brucei, X-Rays, Protozoan Proteins, Crystallography, X-Ray, Spodoptera, Catalytic Domain, Sf9 Cells
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