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PDBsum entry 1d4h
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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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Optimization of p1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors.
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Authors
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H.O.Andersson,
K.Fridborg,
S.Löwgren,
M.Alterman,
A.Mühlman,
M.Björsne,
N.Garg,
I.Kvarnström,
W.Schaal,
B.Classon,
A.Karlén,
U.H.Danielsson,
G.Ahlsén,
U.Nillroth,
L.Vrang,
B.Oberg,
B.Samuelsson,
A.Hallberg,
T.Unge.
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Ref.
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Eur J Biochem, 2003,
270,
1746-1758.
[DOI no: ]
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PubMed id
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Abstract
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HIV-1 protease is an important target for treatment of AIDS, and efficient drugs
have been developed. However, the resistance and negative side effects of the
current drugs has necessitated the development of new compounds with different
binding patterns. In this study, nine C-terminally duplicated HIV-1 protease
inhibitors were cocrystallised with the enzyme, the crystal structures analysed
at 1.8-2.3 A resolution, and the inhibitory activity of the compounds
characterized in order to evaluate the effects of the individual modifications.
These compounds comprise two central hydroxy groups that mimic the geminal
hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is
located between the delta-oxygen atoms of the two catalytic aspartic acid
residues, and the other in the gauche position relative to the first. The
asymmetric binding of the two central inhibitory hydroxyls induced a small
deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The
study shows that the protease molecule could accommodate its structure to
different sizes of the P2/P2' groups. The structural alterations were, however,
relatively conservative and limited. The binding capacity of the S3/S3' sites
was exploited by elongation of the compounds with groups in the P3/P3' positions
or by extension of the P1/P1' groups. Furthermore, water molecules were shown to
be important binding links between the protease and the inhibitors. This study
produced a number of inhibitors with Ki values in the 100 picomolar range.
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Figure 1.
Fig. 1. Orientation of the inhibitor in the active site and
arrangement of the central vicinal hydroxyls (stereo view). The
figure shows the structure of the asymmetric compound 3 as it is
arranged in the HIV-1 protease active site. The electron density
map indicates a unique orientation of the inhibitor and the
whole protease–inhibitor complex in the crystal lattice. The
density also indicates an  90% unique
orientation of the central vicinal hydroxy groups in the complex
with this compound. The Fo–Fc electron density map was
calculated at 2.0 Å resolution with the inhibitor compound
omitted, and contoured at 2.5  .
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Figure 2.
Fig. 2. Positioning of the inhibitor in the active site and
hydrogen-bond network. One of the inhibitor hydroxyls has
extensive contacts with the catalytic Asp25/Asp125. The
hydrogen-bond distances are short (2.7–2.8 Å). The
gauche hydroxy group is hydrogen-bonded to one of the catalytic
aspartate residues. Gly27/Gly127 contribute to the active-site
hydrogen-bond network by donation of hydrogens via the
main-chain amide groups. These two compounds 1 and 2 represent
the two groups of inhibitors in this study. Compound 1 (A) has
10 and compound 2 (B) has 8 hydrogen-bond donors/acceptors. In
the latter case, two water molecules remain co-ordinated to the
G48/G148 carbonyl groups after complex formation.
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The above figures are
reprinted
by permission from the Federation of European Biochemical Societies:
Eur J Biochem
(2003,
270,
1746-1758)
copyright 2003.
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