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

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.

• Authors: Johan Zeelen, Monique van Straaten, Joseph Verdi, Alexander Hempelmann, Hamidreza Hashemi, Kathryn Perez, Philip D Jeffrey, Silvan Hälg, Natalie Wiedemar, Pascal Mäser, F Nina Papavasiliou, C Erec Stebbins
• Journal: Nature microbiology (Nat Microbiol) Vol. 6 Issue 3 Pg. 392-400 (03 2021) ISSN: 2058-5276 [Electronic] England
• PMID: 33462435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Trypanocidal Agents
• VSGsur protein, Trypanosoma brucei rhodesiense
• Variant Surface Glycoproteins, Trypanosoma
• Suramin

Topics

• Antigenic Variation (drug effects, immunology)
• Binding Sites
• Crystallography, X-Ray
• Drug Resistance (genetics, immunology)
• Endocytosis (genetics)
• Immune Evasion
• Mutation
• Protein Binding
• Protein Conformation
• Suramin (metabolism, toxicity)
• Trypanocidal Agents (metabolism, toxicity)
• Trypanosoma brucei rhodesiense (chemistry, drug effects, immunology, metabolism)
• Trypanosomiasis, African (parasitology)
• Variant Surface Glycoproteins, Trypanosoma (chemistry, genetics, metabolism)