Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser

Lars Redecke; Karol Nass; Daniel P. DePonte; Thomas A. White; Dirk Rehders; Anton Barty; Francesco Stellato; Mengning Liang; Thomas R M Barends; Sébastien Boutet; Garth J. Williams; Marc Messerschmidt; M. Marvin Seibert; Andrew Aquila; David Arnlund; Sasa Bajt; Torsten B. Barth; Michael J. Bogan; Carl Caleman; Tzu Chiao Chao; R. Bruce Doak; Holger Fleckenstein; Matthias Frank; Raimund Fromme; Lorenzo Galli; Ingo Grotjohann; Mark S. Hunter; Linda C. Johansson; Stephan Kassemeyer; Gergely Katona; Richard Kirian; Rudolf Koopmann; Chris Kupitz; Lukas Lomb; Andrew V. Martin; Stefan Mogk; Richard Neutze; Robert L. Shoeman; Jan Steinbrener; Nicusor Timneanu; Dingjie Wang; Uwe Weierstall; Nadia Zatsepin; John Spence; Petra Fromme; Ilme Schlichting; Michael Duszenko; Christian Betzel; Henry N. Chapman

doi:10.1126/science.1229663

Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser

Lars Redecke, Karol Nass, Daniel P. DePonte, Thomas A. White, Dirk Rehders, Anton Barty, Francesco Stellato, Mengning Liang, Thomas R M Barends, Sébastien Boutet, Garth J. Williams, Marc Messerschmidt, M. Marvin Seibert, Andrew Aquila, David Arnlund, Sasa Bajt, Torsten B. Barth, Michael J. Bogan, Carl Caleman, Tzu Chiao ChaoR. Bruce Doak, Holger Fleckenstein, Matthias Frank, Raimund Fromme, Lorenzo Galli, Ingo Grotjohann, Mark S. Hunter, Linda C. Johansson, Stephan Kassemeyer, Gergely Katona, Richard Kirian, Rudolf Koopmann, Chris Kupitz, Lukas Lomb, Andrew V. Martin, Stefan Mogk, Richard Neutze, Robert L. Shoeman, Jan Steinbrener, Nicusor Timneanu, Dingjie Wang, Uwe Weierstall, Nadia Zatsepin, John Spence, Petra Fromme, Ilme Schlichting, Michael Duszenko, Christian Betzel, Henry N. Chapman

Research output: Contribution to journal › Article › peer-review

363 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	227-230
Number of pages	4
Journal	Science
Volume	339
Issue number	6116
DOIs	https://doi.org/10.1126/science.1229663
State	Published - Jan 11 2013

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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. B., Bogan, M. J., Caleman, C., ... Chapman, H. N. (2013). Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser. Science, 339(6116), 227-230. https://doi.org/10.1126/science.1229663

Redecke, L, Nass, K, DePonte, DP, White, TA, Rehders, D, Barty, A, Stellato, F, Liang, M, Barends, TRM, Boutet, S, Williams, GJ, Messerschmidt, M, Seibert, MM, Aquila, A, Arnlund, D, Bajt, S, Barth, TB, Bogan, MJ, Caleman, C, Chao, TC, Doak, RB, Fleckenstein, H, Frank, M, Fromme, R, Galli, L, Grotjohann, I, Hunter, MS, Johansson, LC, Kassemeyer, S, Katona, G, Kirian, R, Koopmann, R, Kupitz, C, Lomb, L, Martin, AV, Mogk, S, Neutze, R, Shoeman, RL, Steinbrener, J, Timneanu, N, Wang, D, Weierstall, U, Zatsepin, N, Spence, J, Fromme, P, Schlichting, I, Duszenko, M, Betzel, C & Chapman, HN 2013, 'Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser', Science, vol. 339, no. 6116, pp. 227-230. https://doi.org/10.1126/science.1229663

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title = "Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser",

abstract = "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.",

author = "Lars Redecke and Karol Nass and DePonte, {Daniel P.} and White, {Thomas A.} and Dirk Rehders and Anton Barty and Francesco Stellato and Mengning Liang and Barends, {Thomas R M} and S{\'e}bastien Boutet and Williams, {Garth J.} and Marc Messerschmidt and Seibert, {M. Marvin} and Andrew Aquila and David Arnlund and Sasa Bajt and Barth, {Torsten B.} and Bogan, {Michael J.} and Carl Caleman and Chao, {Tzu Chiao} and Doak, {R. Bruce} and Holger Fleckenstein and Matthias Frank and Raimund Fromme and Lorenzo Galli and Ingo Grotjohann and Hunter, {Mark S.} and Johansson, {Linda C.} and Stephan Kassemeyer and Gergely Katona and Richard Kirian and Rudolf Koopmann and Chris Kupitz and Lukas Lomb and Martin, {Andrew V.} and Stefan Mogk and Richard Neutze and Shoeman, {Robert L.} and Jan Steinbrener and Nicusor Timneanu and Dingjie Wang and Uwe Weierstall and Nadia Zatsepin and John Spence and Petra Fromme and Ilme Schlichting and Michael Duszenko and Christian Betzel and Chapman, {Henry N.}",

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T1 - Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser

AU - Redecke, Lars

AU - Nass, Karol

AU - DePonte, Daniel P.

AU - White, Thomas A.

AU - Rehders, Dirk

AU - Barty, Anton

AU - Stellato, Francesco

AU - Liang, Mengning

AU - Barends, Thomas R M

AU - Boutet, Sébastien

AU - Williams, Garth J.

AU - Messerschmidt, Marc

AU - Seibert, M. Marvin

AU - Aquila, Andrew

AU - Arnlund, David

AU - Bajt, Sasa

AU - Barth, Torsten B.

AU - Bogan, Michael J.

AU - Caleman, Carl

AU - Chao, Tzu Chiao

AU - Doak, R. Bruce

AU - Fleckenstein, Holger

AU - Frank, Matthias

AU - Fromme, Raimund

AU - Galli, Lorenzo

AU - Grotjohann, Ingo

AU - Hunter, Mark S.

AU - Johansson, Linda C.

AU - Kassemeyer, Stephan

AU - Katona, Gergely

AU - Kirian, Richard

AU - Koopmann, Rudolf

AU - Kupitz, Chris

AU - Lomb, Lukas

AU - Martin, Andrew V.

AU - Mogk, Stefan

AU - Neutze, Richard

AU - Shoeman, Robert L.

AU - Steinbrener, Jan

AU - Timneanu, Nicusor

AU - Wang, Dingjie

AU - Weierstall, Uwe

AU - Zatsepin, Nadia

AU - Spence, John

AU - Fromme, Petra

AU - Schlichting, Ilme

AU - Duszenko, Michael

AU - Betzel, Christian

AU - Chapman, Henry N.

PY - 2013/1/11

Y1 - 2013/1/11

N2 - 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.

AB - 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.

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Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser

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Trypanosoma brucei procathepsin B solved from 40 fs free-electron laser pulse data by serial femtosecond X-ray crystallography

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Natively inhibited trypanosoma brucei cathepsin B structure determined by using an x-ray laser

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Trypanosoma brucei procathepsin B solved from 40 fs free-electron laser pulse data by serial femtosecond X-ray crystallography

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