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    Role of invariant Thr80 in human immunodeficiency virus type 1 protease structure, function, and viral infectivity

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    Authors
    Foulkes-Murzycki, Jennifer E.
    Prabu-Jeyabalan, Moses
    Cooper, Deyna
    Henderson, Gavin J.
    Harris, Janera
    Swanstrom, Ronald I.
    Schiffer, Celia A.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2006-07-01
    Keywords
    Amino Acid Substitution
    Aspartic Endopeptidases
    HIV Protease
    HIV Protease Inhibitors
    HIV-1
    *Models, Molecular
    Protein Structure, Secondary
    Protein Structure, Tertiary
    Structure-Activity Relationship
    Substrate Specificity
    Tryptophan
    Life Sciences
    Medicine and Health Sciences
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    Abstract
    Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. While the importance of conserved active-site residues is easily understood, the role of other invariant residues is not. This work focuses on invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. In a previous study, we postulated, on the basis of a molecular dynamics simulation of the unliganded protease, that Thr80 may play a role in the mobility of the flaps of protease. In the present study, both experimental and computational methods were used to study the role of Thr80 in HIV protease. Three protease variants (T80V, T80N, and T80S) were examined for changes in structure, dynamics, enzymatic activity, affinity for protease inhibitors, and viral infectivity. While all three variants were structurally similar to the wild type, only T80S was functionally similar. Both T80V and T80N had decreased the affinity for saquinavir. T80V significantly decreased the ability of the enzyme to cleave a peptide substrate but maintained infectivity, while T80N abolished both activity and viral infectivity. Additionally, T80N decreased the conformational flexibility of the flap region, as observed by simulations of molecular dynamics. Taken together, these data indicate that HIV-1 protease functions best when residue 80 is a small polar residue and that mutations to other amino acids significantly impair enzyme function, possibly by affecting the flexibility of the flap domain.
    Source
    J Virol. 2006 Jul;80(14):6906-16. Link to article on publisher's site
    DOI
    10.1128/JVI.01900-05
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/38652
    PubMed ID
    16809296
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.01900-05
    Scopus Count
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    UMass Chan Faculty and Researcher Publications
    Schiffer Lab Publications

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