Faculty Collaboration Database

Tyrosine-sulfated V2 peptides inhibit HIV-1 infection via coreceptor mimicry. EBioMedicine 2016 Aug;10:45-54

Date

07/09/2016

Pubmed ID

27389109

Pubmed Central ID

PMC5006643

DOI

10.1016/j.ebiom.2016.06.037

Scopus ID

2-s2.0-85028268790   8 Citations

Abstract

Tyrosine sulfation is a post-translational modification that facilitates protein-protein interaction. Two sulfated tyrosines (Tys173 and Tys177) were recently identified within the second variable (V2) loop of the major HIV-1 envelope glycoprotein, gp120, and shown to contribute to stabilizing the intramolecular interaction between V2 and the third variable (V3) loop. Here, we report that tyrosine-sulfated peptides derived from V2 act as structural and functional mimics of the CCR5 N-terminus and potently block HIV-1 infection. Nuclear magnetic and surface plasmon resonance analyses indicate that a tyrosine-sulfated V2 peptide (pV2α-Tys) adopts a CCR5-like helical conformation and directly interacts with gp120 in a CD4-dependent fashion, competing with a CCR5 N-terminal peptide. Sulfated V2 mimics, but not their non-sulfated counterparts, inhibit HIV-1 entry and fusion by preventing coreceptor utilization, with the highly conserved C-terminal sulfotyrosine, Tys177, playing a dominant role. Unlike CCR5 N-terminal peptides, V2 mimics inhibit a broad range of HIV-1 strains irrespective of their coreceptor tropism, highlighting the overall structural conservation of the coreceptor-binding site in gp120. These results document the use of receptor mimicry by a retrovirus to occlude a key neutralization target site and provide leads for the design of therapeutic strategies against HIV-1.

Author List

Cimbro R, Peterson FC, Liu Q, Guzzo C, Zhang P, Miao H, Van Ryk D, Ambroggio X, Hurt DE, De Gioia L, Volkman BF, Dolan MA, Lusso P

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Anti-HIV Agents
Binding Sites
CD4 Antigens
HIV Envelope Protein gp120
HIV Infections
HIV-1
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Mimicry
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments
Protein Binding
Protein Conformation
Receptors, CCR5
Tyrosine