Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody
Open accessPreprint — published as 10.7554/elife.100066.3 · Paper page
Abstract
African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Highly accurate protein structure prediction for the human proteome
Tunyasuvunakool, K., Adler, J., Wu, Z., Green, T., Zielinski, M., Žídek, A., Bridgland, A., Cowie, A., Meyer, C., Laydon, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03828-1 · Cited by 3,025 · cited 1× · see citing works
“…six copies of the structure of the Tco PYK monomer (chain D, PDB ID: 6SU1) devoid of the B domain given its notorious flexibility, and (ii) six copies of an AlphaFold2 ( Jumper et al., 2021 ; Tunyasuvunakool et al., 2021 ) model of sdAb42 (of which the CDR1 was removed due to poor pLDDT scores).”
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- Authors
- Pinto Torres, J. E., Claes, M., Hendrickx, R., Yuan, M., Smiejkowska, N., Van Wielendaele, P., Hacisuleyman, A., De Winter, H., Muyldermans, S., Michels, P. A., Walkinshaw, M. D., Versées, W., Caljon, G., Magez, S., & Sterckx, Y. G.-J.
- Affiliations
- University of Antwerp (BE)
- University of Edinburgh (GB)
- University of Lausanne (CH)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Sterckx, Yann G.-J.
- ORCID
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2024-06-15
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4409003966
- Cited by
- 3
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- Fonds Wetenschappelijk Onderzoek (1137622N, G013518N)
- Universiteit Gent (BOF.STG.2018.0009.01/01N01518)
- Vrije Universiteit Brussel (SRP95)
- Universiteit Antwerpen (41391)
- Topics
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- allosteric inhibition, nanobodies, African trypanosomes, trypanocidal drugs, glycolysis, parasite energy metabolism, enzyme kinetics, drug resistance
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