Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease

Mi Li, Alla Gustchina, Krisztina Matúz, Jozsef Tözsér, Sirilak Namwong, Nathan E. Goldfarb, Ben M. Dunn, Alexander Wlodawer

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K i, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place. Structured digital abstract and by () Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus (XMRV) and a number of potential inhibitors have been investigated by biochemical and structural techniques. Binding data were obtained for a number of compounds and crystal structures of the complexes of XMRV PR with TL-3, amprenavir, and pepstatin A were solved at high resolution

Original languageEnglish
Pages (from-to)4413-4424
Number of pages12
JournalFEBS Journal
Volume278
Issue number22
DOIs
Publication statusPublished - Nov 1 2011

Keywords

  • aspartic protease
  • enzyme inhibition
  • inhibitor binding
  • retrovirus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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