Structure of trypanosome coat protein VSGsur and function in suramin resistance
- 18 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 6 (3), 392-400
- https://doi.org/10.1038/s41564-020-00844-1
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.Keywords
Funding Information
- Deutsches Krebsforschungszentrum
- European Molecular Biology Organization
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_185163, 310030_185163, 310030_185163)
This publication has 54 references indexed in Scilit:
- High-throughput decoding of antitrypanosomal drug efficacy and resistanceNature, 2012
- Presenting your structures: theCCP4mgmolecular-graphics softwareActa crystallographica. Section D, Structural biology, 2011
- Overview of theCCP4 suite and current developmentsActa crystallographica. Section D, Structural biology, 2011
- Features and development of CootActa crystallographica. Section D, Structural biology, 2010
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa crystallographica. Section D, Structural biology, 2010
- The development of drugs for treatment of sleeping sickness: a historical reviewParasites & Vectors, 2010
- A Histone Methyltransferase Modulates Antigenic Variation in African TrypanosomesPLoS Biology, 2008
- Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7Nature Protocols, 2008
- A short history of SHELXActa Crystallographica Section A Foundations of Crystallography, 2007
- Distribution of Suramin, an Antitrypanosomal Drug, across the Blood-Brain and Blood-Cerebrospinal Fluid Interfaces in Wild-Type and P-Glycoprotein Transporter-Deficient MiceAntimicrobial Agents and Chemotherapy, 2007