Journal Article

PUBDB-2020-00621

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors

Nass, K.CFEL* ; Redecke, L.Extern*DESY* ; Perbandt, M.Extern*EMBL* ; Yefanov, O.CFEL*EMBL*DESY* ; Klinge, M.Extern*EMBL* ; Koopmann, R. ; Stellato, F.Extern* ; Gabdulkhakov, A.Extern*EMBL* ; Schönherr, R.Extern*DESY* ; Rehders, D.Extern*EMBL* ; Lahey-Rudolph, J. M. ; Aquila, A.Extern* ; Barty, A.CFEL*DESY* ; Basu, S.Extern*EMBL* ; Doak, R. B.Extern*MPG*XFEL.EU* ; Duden, R. ; Frank, M.Extern* ; Fromme, R.CFEL*Extern* ; Kassemeyer, S.Extern* ; Katona, G.Extern*EMBL* ; Kirian, R.DESY* ; Liu, H. ; Majoul, I. ; Martin-Garcia, J. M. ; Messerschmidt, M.Extern*XFEL.EU* ; Shoeman, R. L. ; Weierstall, U.Extern* ; Westenhoff, S.Extern*EMBL* ; White, T.CFEL*DESY* ; Williams, G. J. ; Yoon, C. H.Extern* ; Zatsepin, N.Extern*XFEL.EU* ; Fromme, P.CFEL*Extern* ; Duszenko, M. ; Chapman, H. N.CFEL*DESY* ; Betzel, C. (Corresponding author)Extern*

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-020-14484-w  doi:10.3204/PUBDB-2020-00621

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.

Note: open access

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Contributing Institute(s):

1. FS-CFEL-1 (Group Leader: Henry Chapman) (CFEL-I)
2. CFEL-Coherent X-Ray Imaging (FS-CFEL-1)
3. beauftragt von UNI (UNI/CUI)
4. beauftragt von FS-CFEL-1 (ASU)
5. DOOR-User (DOOR ; HAS-User)
6. Universität zu Lübeck (U Lübeck)

Research Program(s):

1. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)
2. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
3. DFG project 194651731 - EXC 1074: Hamburger Zentrum für ultraschnelle Beobachtung (CUI): Struktur, Dynamik und Kontrolle von Materie auf atomarer Skala (194651731) (194651731)
4. DFG project 390715994 - EXC 2056: CUI: Advanced Imaging of Matter (390715994) (390715994)

Experiment(s):

1. Experiments at CFEL
2. Measurement at external facility

Appears in the scientific report 2020

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Database coverage:
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