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, Bruce; Duden, R.; Frank, M.; Fromme, R.; Kassemeyer, Stephan; Katona, G.; Kirian, R.; Liu, H.; Majoul, I.; Martin-Garcia, J. M.; Messerschmidt, M.; Shoeman, Robert 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

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

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Doak, Bruce
Coherent diffractive imaging, Max Planck Institute for Medical Research, Max Planck Society;
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Kassemeyer, Stephan
Coherent diffractive imaging, Max Planck Institute for Medical Research, Max Planck Society;
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Shoeman, Robert L.
Analytical Protein Biochemistry, Max Planck Institute for Medical Research, Max Planck Society;
Coherent diffractive imaging, Max Planck Institute for Medical Research, Max Planck Society;
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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https://doi.org/10.1038/s41467-020-14484-w
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Citation

Nass, K., Redecke, L., Perbandt, M., Yefanov, O., Klinge, M., Koopmann, R., et al. (2020). In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors. Nature Communications, 11(1): 620, pp. 1-13. doi:10.1038/s41467-020-14484-w.

Cite as: https://hdl.handle.net/21.11116/0000-0005-94E8-E

Abstract

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.