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Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance
Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here that VSGsur binds tightly to suramin...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116837/ https://www.ncbi.nlm.nih.gov/pubmed/33462435 http://dx.doi.org/10.1038/s41564-020-00844-1 |
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author | Zeelen, Johan van Straaten, Monique Verdi, Joseph Hempelmann, Alexander Hashemi, Hamidreza Perez, Kathryn Jeffrey, Philip D. Hälg, Silvan Wiedemar, Natalie Mäser, Pascal Papavasiliou, F. Nina Stebbins, C. Erec |
author_facet | Zeelen, Johan van Straaten, Monique Verdi, Joseph Hempelmann, Alexander Hashemi, Hamidreza Perez, Kathryn Jeffrey, Philip D. Hälg, Silvan Wiedemar, Natalie Mäser, Pascal Papavasiliou, F. Nina Stebbins, C. Erec |
author_sort | Zeelen, Johan |
collection | PubMed |
description | Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here 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. |
format | Online Article Text |
id | pubmed-7116837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-71168372021-07-18 Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance Zeelen, Johan van Straaten, Monique Verdi, Joseph Hempelmann, Alexander Hashemi, Hamidreza Perez, Kathryn Jeffrey, Philip D. Hälg, Silvan Wiedemar, Natalie Mäser, Pascal Papavasiliou, F. Nina Stebbins, C. Erec Nat Microbiol Article Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here 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. 2021-03-01 2021-01-18 /pmc/articles/PMC7116837/ /pubmed/33462435 http://dx.doi.org/10.1038/s41564-020-00844-1 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Zeelen, Johan van Straaten, Monique Verdi, Joseph Hempelmann, Alexander Hashemi, Hamidreza Perez, Kathryn Jeffrey, Philip D. Hälg, Silvan Wiedemar, Natalie Mäser, Pascal Papavasiliou, F. Nina Stebbins, C. Erec Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title | Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title_full | Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title_fullStr | Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title_full_unstemmed | Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title_short | Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance |
title_sort | structure of trypanosome coat protein vsgsur and function in suramin resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116837/ https://www.ncbi.nlm.nih.gov/pubmed/33462435 http://dx.doi.org/10.1038/s41564-020-00844-1 |
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