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Structure of trypanosome coat protein VSGsur and function in suramin resistance.

Zeelen J, van Straaten M, Verdi J, Hempelmann A, Hashemi H, Perez K, Jeffrey PD, Hälg S, Wiedemar N, Mäser P, Papavasiliou FN, Stebbins CE
Nat Microbiol 6 392-400 (2021)
Related entries: 6z79, 6z7b, 6z7c, 6z7d, 6z7e, 6z8g

Cited: 9 times
EuropePMC logo PMID: 33462435

Abstract

Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly 100 yr. Recent studies revealed that trypanosome strains that express the variant surface glycoprotein (VSG) VSGsur possess heightened resistance to suramin. Here, we show that VSGsur binds tightly to suramin but other VSGs do not. By solving high-resolution crystal structures of VSGsur and VSG13, we also demonstrate that these VSGs define a structurally divergent subgroup of the coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.

Reviews citing this publication (4)

  1. The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids. Borges AR, Link F, Engstler M, Jones NG. Front Cell Dev Biol 9 720536 (2021)
  2. Learning from Yeast about Mitochondrial Carriers. Mentel M, Chovančíková P, Zeman I, Polčic P. Microorganisms 9 2044 (2021)
  3. Systematic Review and Meta-Analysis on Human African Trypanocide Resistance. Kasozi KI, MacLeod ET, Welburn SC. Pathogens 11 1100 (2022)
  4. Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies. Jamabo M, Mahlalela M, Edkins AL, Boshoff A. Int J Mol Sci 24 12529 (2023)

Articles citing this publication (5)

  1. Structural similarities between the metacyclic and bloodstream form variant surface glycoproteins of the African trypanosome. Chandra M, Đaković S, Foti K, Zeelen JP, van Straaten M, Aresta-Branco F, Tihon E, Lübbehusen N, Ruppert T, Glover L, Papavasiliou FN, Stebbins CE. PLoS Negl Trop Dis 17 e0011093 (2023)
  2. A structural classification of the variant surface glycoproteins of the African trypanosome. Đaković S, Zeelen JP, Gkeka A, Chandra M, van Straaten M, Foti K, Zhong J, Vlachou EP, Aresta-Branco F, Verdi JP, Papavasiliou FN, Stebbins CE. PLoS Negl Trop Dis 17 e0011621 (2023)
  3. Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency. Chang MY, Hsu SH, Ma LY, Chou LF, Hung CC, Tian YC, Yang CW. Int J Mol Sci 23 8499 (2022)
  4. Suramin action in African trypanosomes involves a RuvB-like DNA helicase. Albisetti A, Hälg S, Zoltner M, Mäser P, Wiedemar N. Int J Parasitol Drugs Drug Resist 23 44-53 (2023)
  5. The role of invariant surface glycoprotein 75 in xenobiotic acquisition by African trypanosomes. Makarov A, Began J, Mautone IC, Pinto E, Ferguson L, Zoltner M, Zoll S, Field MC. Microb Cell 10 18-35 (2023)


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