PDBsum entry 6z8h

Membrane protein

PDB id: 6z8h

Contents

Protein chains

351 a.a.

Ligands

BMA-MAN ×2

NAG ×4

SO4

Waters ×421

PDB id:

6z8h

Name:

Membrane protein

Title:

Crystal structure of variant surface glycoprotein vsg13

Structure:

Variant surface glycoprotein mitat 1.13. Chain: a, b. Other_details: glycosylated at n260

Source:

Trypanosoma brucei. Organism_taxid: 5691

Resolution:

1.38Å R-factor: 0.218 R-free: 0.241

Authors:

C.E.Stebbins,A.Hempelmann,M.Van Straaten,J.Zeelen

Key ref:

J.Zeelen et al. (2021). Structure of trypanosome coat protein VSGsur and function in suramin resistance. Nat Microbiol, 6, 392-400. PubMed id: 33462435 DOI: 10.1038/s41564-020-00844-1

Date:

02-Jun-20 Release date: 17-Mar-21

Protein chains

Q58NS4  (Q58NS4_9TRYP) -  Variant surface glycoprotein MITat 1.13 from Trypanosoma brucei

Seq: 499 a.a.

Struc: 351 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1038/s41564-020-00844-1

Nat Microbiol 6:392-400 (2021)

PubMed id: 33462435

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

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.

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.