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PDBsum entry 3fx5
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Hydrolase/hydrolase inhibitor
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PDB id
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3fx5
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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 HIV-1 protease in complex with potent inhibitor kni-272 determined by high-Resolution x-Ray and neutron crystallography.
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Authors
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M.Adachi,
T.Ohhara,
K.Kurihara,
T.Tamada,
E.Honjo,
N.Okazaki,
S.Arai,
Y.Shoyama,
K.Kimura,
H.Matsumura,
S.Sugiyama,
H.Adachi,
K.Takano,
Y.Mori,
K.Hidaka,
T.Kimura,
Y.Hayashi,
Y.Kiso,
R.Kuroki.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
4641-4646.
[DOI no: ]
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PubMed id
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Abstract
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HIV-1 protease is a dimeric aspartic protease that plays an essential role in
viral replication. To further understand the catalytic mechanism and inhibitor
recognition of HIV-1 protease, we need to determine the locations of key
hydrogen atoms in the catalytic aspartates Asp-25 and Asp-125. The structure of
HIV-1 protease in complex with transition-state analog KNI-272 was determined by
combined neutron crystallography at 1.9-A resolution and X-ray crystallography
at 1.4-A resolution. The resulting structural data show that the catalytic
residue Asp-25 is protonated and that Asp-125 (the catalytic residue from the
corresponding diad-related molecule) is deprotonated. The proton on Asp-25 makes
a hydrogen bond with the carbonyl group of the allophenylnorstatine (Apns) group
in KNI-272. The deprotonated Asp-125 bonds to the hydroxyl proton of Apns. The
results provide direct experimental evidence for proposed aspects of the
catalytic mechanism of HIV-1 protease and can therefore contribute substantially
to the development of specific inhibitors for therapeutic application.
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Figure 1.
Tertiary structure of HIV-1 protease determined by neutron
diffraction. The HIV protease dimer is shown by a ball and stick
model; water molecules and bound inhibitor are shown by
space-filling representation. Hydrogen and deuterium atoms are
colored gray. Carbon (green), oxygen (red), nitrogen (blue), and
sulfur (yellow) atoms in protease are indicated. Carbon atoms in
KNI-272 are colored dark gray. Figs. 1, 2, and 4 were made by
using the program Pymol (www.pymol.org).
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Figure 3.
Schematic diagram of the interaction between HIV-1 protease
and KNI-272 (bold lines). Hydrogen bonds are shown by broken
lines. Asterisks indicate the hydrogen atoms replaced with
deuterium atom (occupancies of deuterium atom are >0.5).
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