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Protein science : a publication of the Protein Society1996; 5(8); 1453-1465; doi: 10.1002/pro.5560050802

Structure of equine infectious anemia virus proteinase complexed with an inhibitor.

Abstract: Equine infectious anemia virus (EIAV), the causative agent of infectious anemia in horses, is a member of the lentiviral family. The virus-encoded proteinase (PR) processes viral polyproteins into functional molecules during replication and it also cleaves viral nucleocapsid protein during infection. The X-ray structure of a complex of the 154G mutant of EIAV PR with the inhibitor HBY-793 was solved at 1.8 A resolution and refined to a crystallographic R-factor of 0.136. The molecule is a dimer in which the monomers are related by a crystallographic twofold axis. Although both the enzyme and the inhibitor are symmetric, the interactions between the central part of the inhibitor and the active site aspartates are asymmetric, and the inhibitor and the two flaps are partially disordered. The overall fold of EIAV PR is very similar to that of other retroviral proteinases. However, a novel feature of the EIAV PR structure is the appearance of the second alpha-helix in the monomer in a position predicted by the structural template for the family of aspartic proteinases. The parts of the EIAV PR with the highest resemblance to human immunodeficiency virus type 1 PR include the substrate-binding sites; thus, the differences in the specificity of both enzymes have to be explained by enzyme-ligand interactions at the periphery of the active site as well.
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Publication Date: 1996-08-01 PubMed ID: 8844837PubMed Central: PMC2143478DOI: 10.1002/pro.5560050802Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research study presents the experimental exploration of the structure of a proteinase from the equine infectious anemia virus (EIAV), and how it interplays with a specific inhibitor. The authors utilized X-ray crystallography to decipher this structure at an atomic level, which offered insights into the similarities between this proteinase and others in retroviruses.

Study Objective and Methodology

  • The main objective of this study was to understand the structure of the equine infectious anemia virus (EIAV) proteinase (PR) and its interaction with an inhibitor (HBY-793). The EIAV PR plays a significant role in viral replication by processing viral polyproteins into functional molecules and cleaving viral nucleocapsid protein.
  • The researchers utilized the tool of X-ray crystallography to achieve this. They specifically examined the complex of the 154G mutant of EIAV PR with the inhibitor at 1.8 A resolution.

Findings and Analysis

  • Upon analysis, the researchers found that EIAV PR is a dimer, a complex of two identical molecules (monomers). The monomers are related by a twofold axis, maintaining a symmetrical structure.
  • Interestingly, despite the symmetric nature of the enzyme and the inhibitor, the interactions between the central part of the inhibitor and the active site aspartates were found to be asymmetrical. Additionally, the inhibitor and the two flaps were partially disordered.
  • The EIAV PR structure shared striking similarities with other retroviral proteinases, but it also had a unique feature: the appearance of the second alpha-helix in the monomer in a position predicted by the structural template for the family of aspartic proteinases.
  • The areas of the EIAV PR most resembling human immunodeficiency virus type 1 PR were the substrate-binding sites. Moreover, the researchers found that differences in the specificity of both enzymes had to be linked also to enzyme-ligand interactions at the periphery of the active site.

Implications of the Study

  • This study deepens our understanding of the structure and functioning of EIAV PR and how inhibitors work against it. This knowledge can play a pivotal role in developing more effective antiviral drugs.
  • By elucidating the similarities and differences between EIAV PR and the similar proteinase in HIV, this research could shed light on new potential lines of approach in HIV/AIDS treatment and prevention.

Cite This Article

APA
Gustchina A, Kervinen J, Powell DJ, Zdanov A, Kay J, Wlodawer A. (1996). Structure of equine infectious anemia virus proteinase complexed with an inhibitor. Protein Sci, 5(8), 1453-1465. https://doi.org/10.1002/pro.5560050802

Publication

Protein science : a publication of the Protein Society
ISSN: 0961-8368
NlmUniqueID: 9211750
Country: United States
Language: English
Volume: 5
Issue: 8
Pages: 1453-1465

Researcher Affiliations

Gustchina, A
  • Macromolecular Structure Laboratory, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Kervinen, J
    Powell, D J
      Zdanov, A
        Kay, J
          Wlodawer, A

            MeSH Terms

            • Amino Acid Sequence
            • Animals
            • Binding Sites
            • Crystallography, X-Ray
            • Endopeptidases / chemistry
            • Endopeptidases / genetics
            • Escherichia coli / genetics
            • HIV Protease Inhibitors / chemistry
            • HIV-1 / chemistry
            • Horses
            • Humans
            • Hydrogen Bonding
            • Infectious Anemia Virus, Equine / enzymology
            • Infectious Anemia Virus, Equine / genetics
            • Molecular Sequence Data
            • Protease Inhibitors / chemistry
            • Protein Structure, Secondary
            • Protein Structure, Tertiary
            • Pyridines / chemistry
            • Recombinant Proteins / chemistry
            • Recombinant Proteins / genetics
            • Recombinant Proteins / isolation & purification
            • Retroviridae Proteins / antagonists & inhibitors
            • Retroviridae Proteins / chemistry
            • Retroviridae Proteins / genetics
            • Sequence Alignment

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            This article has been cited 15 times.
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