Back to Search
Start Over
Structure of trypanosome coat protein VSGsur and function in suramin resistance
- Source :
- Nature microbiology
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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. The co-crystal structure of VSGsur with the trypanocidal compound suramin directly links the binding of the drug to the resistance phenotype displayed by strains of Trypanosoma brucei expressing VSGsur. Therefore, VSGs can have a function beyond that of antigenic variation.
- Subjects :
- Trypanosoma brucei rhodesiense
Microbiology (medical)
Protein Conformation
Suramin
Immunology
Drug Resistance
Plasma protein binding
Trypanosoma brucei
Crystallography, X-Ray
Applied Microbiology and Biotechnology
Microbiology
Article
03 medical and health sciences
Protein structure
parasitic diseases
polycyclic compounds
Genetics
medicine
Antigenic variation
Binding site
Immune Evasion
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
biology
030306 microbiology
Chemistry
Cell Biology
medicine.disease
biology.organism_classification
Antigenic Variation
Trypanocidal Agents
Endocytosis
3. Good health
Cell biology
Trypanosomiasis, African
Mutation
Glycoprotein
Trypanosomiasis
Variant Surface Glycoproteins, Trypanosoma
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 20585276
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Nature Microbiology
- Accession number :
- edsair.doi.dedup.....6de7bcea833b26e631f61eb165643ccd