In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors

Nass, Karol; Redecke, Lars; Perbandt, M.; Yefanov, O.; Klinge, M.; Koopmann, R.; Stellato, F.; Gabdulkhakov, A.; Schönherr, R.; Rehders, D.; Lahey-Rudolph, J. M.; Aquila, A.; Barty, A.; Basu, S.; Doak, R. B.; Duden, R.; Frank, M.; Fromme, R.; Kassemeyer, S.; Katona, G.; Kirian, R.; Liu, H.; Majoul, I.; Martin-Garcia, J. M.; Messerschmidt, M.; Shoeman, R. L.; Weierstall, U.; Westenhoff, S.; White, T. A.; Williams, G. J.; Yoon, C. H.; Zatsepin, N.; Fromme, P.; Duszenko, M.; Chapman, H. N.; Betzel, C.

doi:10.1038/s41467-020-14484-w

Title: In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors

Journal Article · 29 January 2020 · Nature Communications

DOI: https://doi.org/10.1038/s41467-020-14484-w · OSTI ID:1603290

^[1]; Redecke, Lars ^[2];

^[3]; Yefanov, O. ^[4]; Klinge, M. ^[5];

^[6]; Stellato, F. ^[7]; Gabdulkhakov, A. ^[8]; Schönherr, R. ^[9]; Rehders, D. ^[10];

^[11]; Aquila, A. ^[12]; Barty, A. ^[4]; Basu, S. ^[13]; Doak, R. B. ^[14]; Duden, R. ^[15];

^[16];

^[17]; Kassemeyer, S. ^[18];

^[19] more »

Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Paul Scherrer Inst. (PSI), Villigen (Switzerland)
Inst. of Biochemistry and Molecular Biology, Hamburg (Germany). Joint Lab. for Structural Biology of Infection and Inflammation; Univ. of Hamburg (Germany); Univ. of Lübeck, at Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Univ. of Lübeck (Germany); Deutsches Elektronen Synchrotron (DESY), Hamburg (Germany)
Univ. of Hamburg, at Deutsches Elektronen-Synchrotron (DESY) (Germany); The Hamburg Centre for Ultrafast Imaging (CUI), Hamburg (Germany)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
Inst. of Biochemistry and Molecular Biology, Hamburg (Germany). Joint Lab. for Structural Biology of Infection and Inflammation; Univ. of Hamburg (Germany); Univ. of Lübeck, at Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); BioAgilytix Europe GmbH, Hamburg (Germany)
Univ. of Tübingen (Germany)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Univ. di Roma Tor Vergata, Rome (Italy); Istituto Nazionale di Fisica Nucleare (INFN), Rome (Italy)
Russian Academy of Sciences, Moscow Region (Russia)
Univ. of Lübeck (Germany); Deutsches Elektronen Synchrotron (DESY), Hamburg (Germany)
Inst. of Biochemistry and Molecular Biology, Hamburg (Germany). Joint Lab. for Structural Biology of Infection and Inflammation; Univ. of Hamburg (Germany); Univ. of Lübeck, at Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); BODE Chemie GmbH, Hamburg (Germany)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Univ. of Lübeck (Germany)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
Arizona State Univ., Tempe, AZ (United States); European Molecular Biology Lab. (EMBL), Grenoble (France)
Arizona State Univ., Tempe, AZ (United States); Max Planck Inst. for Medical Research, Heidelberg (Germany)
Univ. of Lübeck (Germany)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Arizona State Univ., Tempe, AZ (United States)
Max-Planck-Inst. for Medical Research, Heidelberg (Germany)
Univ. of Gothenburg (Sweden)
Arizona State Univ., Tempe, AZ (United States); Beijing Computational Science Research Center (China)
SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS); Arizona State Univ., Tempe, AZ (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS); Brookhaven National Lab. (BNL), Upton, NY (United States)
Arizona State Univ., Tempe, AZ (United States); La Trobe Univ., VIC (Australia)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); The Hamburg Centre for Ultrafast Imaging (CUI), Hamburg (Germany); Univ. of Hamburg (Germany)

Sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei (Tb). Inosine-5’-monophosphate dehydrogenase (IMPDH) has been proposed as a potential drug target, since it maintains the balance between guanylate deoxynucleotide and ribonucleotide levels that is pivotal for the parasite. Here we report the structure of TbIMPDH at room temperature utilizing free-electron laser radiation on crystals grown in living insect cells. The 2.80 Å resolution structure reveals the presence of ATP and GMP at the canonical sites of the Bateman domains, the latter in a so far unknown coordination mode. Consistent with previously reported IMPDH complexes harboring guanosine nucleotides at the second canonical site, TbIMPDH forms a compact oligomer structure, supporting a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity. The oligomeric TbIMPDH structure we present here reveals the potential of in cellulo crystallization to identify genuine allosteric co-factors from a natural reservoir of specific compounds.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Deutsche Forschungsgemeinschaft (DFG); Helmholtz Excellence Network; National Science Foundation (NSF); German Federal Ministry for Education and Research (BMBF); Joachim-Herz-Stiftung Hamburg; USDOE Laboratory Directed Research and Development (LDRD) Program; Swedish Research Council (VR); Knut and Alice Wallenberg Foundation

Grant/Contract Number:: SC0012704; AC52-07NA27344

OSTI ID:: 1603290

Alternate ID(s):: OSTI ID: 1605174; OSTI ID: 2007604

Report Number(s):: BNL--213686-2020-JAAM

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Accurate determination of segmented X-ray detector geometry Yefanov, Oleksandr; Mariani, Valerio; Gati, Cornelius Optics Express, Vol. 23, Issue 22 https://doi.org/10.1364/oe.23.028459	journal	January 2015
Serial femtosecond crystallography: the first five years Schlichting, Ilme IUCrJ, Vol. 2, Issue 2, p. 246-255 https://doi.org/10.1107/S205225251402702X	journal	February 2015
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Femtosecond X-ray protein nanocrystallography Chapman, Henry N.; Fromme, Petra; Barty, Anton Nature, Vol. 470, Issue 7332, p. 73-77 https://doi.org/10.1038/nature09750	journal	February 2011
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