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PDBsum entry 1vij
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Aspartyl protease
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PDB id
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1vij
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of hoe/bay 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--Structure/function relationship and influence of crystal packing.
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Authors
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G.Lange-Savage,
H.Berchtold,
A.Liesum,
K.H.Budt,
A.Peyman,
J.Knolle,
J.Sedlacek,
M.Fabry,
R.Hilgenfeld.
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Ref.
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Eur J Biochem, 1997,
248,
313-322.
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PubMed id
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Abstract
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Human immunodeficiency virus 1 (HIV-1) protease is a prime target in the search
for drugs to combat the AIDS virus. The enzyme functions as a C2-symmetric
dimer, cleaving the gag and gag-pol viral polyproteins at distinct sites. The
possession of a twofold axis passing through the active site, has led to the
design of C2-symmetrical inhibitors in the form of substrate-based
transition-state analogs. One of the most active compounds of this class of
inhibitors is HOE/BAY 793, which contains a vicinal diol central unit [Budt,
K.-H., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. &
Stowasser, B. & Winkler, I. (1990) European Patent application EP0428,849;
Budt, K.-H., Hansen, J., Knolle, J., Meichsner, C., Ruppert, D., Paessens, A.
& Stowasser B. (1993) IXth International Conference on AIDS; Budt, K.-H.,
Peyman, A., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D.
& Stowasser, B. (1995) Bioorg. Med. Chem. 3, 559-571.] The structure of this
inhibitor bound to HIV-1 protease, in two different crystal forms, has been
solved at 0.24-nm resolution using X-ray crystallography. In both forms, the
details of the inhibitor-protease interactions revealed an overall asymmetric
binding mode, especially between the central diol unit and the active-site
aspartates. The main binding interactions comprise several specific H-bonds and
hydrophobic contacts, which rationalize many of the characteristics of the
structure/activity relationship in the class of vicinal diol inhibitors. In a
general analysis of the mobility of the flap regions, which cover the active
site and participate directly in binding, using our structures and the HIV
protease models present in the Brookhaven databank, we found that in most
structures the flexibility of the flaps is limited by local crystal contacts.
However, in one of the structures presented here, no significant crystal
contacts to the flap regions were present, and as a result the flexibility of
the inhibitor bound flaps increased significantly. This suggests that the
mobility and conformational flexibility of the flap residues are important in
the functioning of HIV-1 protease, and must be considered in the future design
of drugs against HIV protease and in structure-based drug design in general.
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Secondary reference #1
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Title
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Erratum. Structure of hoe/bay 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--Structure/function relationship and influence of crystal packing
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Authors
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G.Lange-Savage,
H.Berchtold,
A.Liesum,
K.H.Budt,
A.Peyman,
J.Knolle,
J.Sedlacek,
M.Fabry,
R.Hilgenfeld.
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Ref.
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eur j biochem, 1997,
249,
912.
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Secondary reference #2
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Title
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Structure-Based inhibitors of HIV-1 protease.
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Authors
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A.Wlodawer,
J.W.Erickson.
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Ref.
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Annu Rev Biochem, 1993,
62,
543-585.
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PubMed id
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