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PDBsum entry 2fnt
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References listed in PDB file
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Key reference
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Title
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Mechanism of substrate recognition by drug-Resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.
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Authors
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M.Prabu-Jeyabalan,
E.A.Nalivaika,
K.Romano,
C.A.Schiffer.
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Ref.
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J Virol, 2006,
80,
3607-3616.
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PubMed id
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Abstract
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Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the
Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an
important target for antiviral therapy. Ligand binding occurs when the flaps
open, allowing access to the active site. This flexibility in flap geometry
makes trapping and crystallizing structural intermediates in substrate binding
challenging. In this study, we report two crystal structures of two HIV-1
protease variants bound with their corresponding nucleocapsid-p1 variant. One of
the flaps in each of these structures exhibits an unusual "intermediate"
conformation. Analysis of the flap-intermediate and flap-closed crystal
structures reveals that the intermonomer flap movements may be asynchronous and
that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate
might close first. This is consistent with our hypothesis that the P3-P1 region
is crucial for substrate recognition. The intermediate conformation is conserved
in both the wild-type and drug-resistant variants. The structural differences
between the variants are evident only when the flaps are closed. Thus, a
plausible structural model for the adaptability of HIV-1 protease to recognize
substrates in the presence of drug-resistant mutations has been proposed.
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Secondary reference #1
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Title
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Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-P1 cleavage site with a v82a drug-Resistant mutation in viral protease.
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Authors
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M.Prabu-Jeyabalan,
E.A.Nalivaika,
N.M.King,
C.A.Schiffer.
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Ref.
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J Virol, 2004,
78,
12446-12454.
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PubMed id
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