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PDBsum entry 6z8h
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Membrane protein
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PDB id
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6z8h
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References listed in PDB file
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Key reference
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Title
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Structure of trypanosome coat protein vsgsur and function in suramin resistance.
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Authors
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J.Zeelen,
M.Van straaten,
J.Verdi,
A.Hempelmann,
H.Hashemi,
K.Perez,
P.D.Jeffrey,
S.Hälg,
N.Wiedemar,
P.Mäser,
F.N.Papavasiliou,
C.E.Stebbins.
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Ref.
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Nat Microbiol, 2021,
6,
392-400.
[DOI no: ]
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PubMed id
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Abstract
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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.
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