Natively Inhibited Trypanosoma brucei Cathepsin B Structure Determined by Using an X-ray Laser

The Trypanosoma brucei cysteine protease cathepsin B (TbCatB), which is involved in host protein degradation, is a promising target to develop new treatments against sleeping sickness, a fatal disease caused by this protozoan parasite. The structure of the mature, active form of TbCatB has so far no...

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Published in:	Science (American Association for the Advancement of Science) Vol. 339; no. 6116; pp. 227 - 230
Main Authors:	Redecke, Lars, Nass, Karol, Deponte, Daniel P., White, Thomas A., Rehders, Dirk, Barty, Anton, Stellato, Francesco, Liang, Mengning, Barends, Thomas R.M., Boutet, Sébastien, Williams, Garth J., Messerschmidt, Marc, Seibert, M. Marvin, Aquila, Andrew, Arnlund, David, Bajt, Sasa, Barth, Torsten, Bogan, Michael J., Caleman, Carl, Chao, Tzu-Chiao, Doak, R. Bruce, Fleckenstein, Holger, Frank, Matthias, Fromme, Raimund, Galli, Lorenzo, Grotjohann, Ingo, Hunter, Mark S., Johansson, Linda C., Kassemeyer, Stephan, Katona, Gergely, Kirian, Richard A., Koopmann, Rudolf, Kupitz, Chris, Lomb, Lukas, Martin, Andrew V., Mogk, Stefan, Neutze, Richard, Shoeman, Robert L., Steinbrener, Jan, Timneanu, Nicusor, Wang, Dingjie, Weierstall, Uwe, Zatsepin, Nadia A., Spence, John C. H., Fromme, Petra, Schlichting, Ilme, Duszenko, Michael, Betzel, Christian, Chapman, Henry N.
Format:	Journal Article
Language:	English
Published:	United States American Association for the Advancement of Science 11-01-2013 The American Association for the Advancement of Science
Subjects:	Activation Active sites Amino Acid Sequence Animals antagonists & inhibitors Atoms Biochemistry Biochemistry and Molecular Biology Biokemi och molekylärbiologi Catalytic Domain Cathepsin B Cathepsin B - antagonists & inhibitors Cathepsin B - chemistry chemistry Crystal structure Crystallization Crystallography Crystallography, X-Ray Crystals Diffraction Electron density Electronic structure Enzyme Precursors Enzyme Precursors - chemistry Enzymes enzymology Glycosylation Inhibitors Lasers Models, Molecular Molecular Molecular biology Molecular Sequence Data NATURAL SCIENCES NATURVETENSKAP Parasitic diseases Proteases Protein Conformation Protozoa Protozoan Proteins Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - chemistry Radiation damage Sf9 Cells Spodoptera Trypanosoma brucei Trypanosoma brucei brucei Trypanosoma brucei brucei - enzymology X-Ray X-ray lasers X-Rays
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Summary:	The Trypanosoma brucei cysteine protease cathepsin B (TbCatB), which is involved in host protein degradation, is a promising target to develop new treatments against sleeping sickness, a fatal disease caused by this protozoan parasite. The structure of the mature, active form of TbCatB has so far not provided sufficient information for the design of a safe and specific drug against T. brucei. By combining two recent innovations, in vivo crystallization and serial femtosecond crystallography, we obtained the room-temperature 2.1 angstrom resolution structure of the fully glycosylated precursor complex of TbCatB. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94550, USA.
ISSN:	0036-8075 1095-9203 1095-9203
DOI:	10.1126/science.1229663