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PDBsum entry 1mu2
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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 HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-Nucleoside inhibitors.
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Authors
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J.Ren,
L.E.Bird,
P.P.Chamberlain,
G.B.Stewart-Jones,
D.I.Stuart,
D.K.Stammers.
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Ref.
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Proc Natl Acad Sci U S A, 2002,
99,
14410-14415.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
96%.
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Abstract
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The HIV-2 serotype of HIV is a cause of disease in parts of the West African
population, and there is evidence for its spread to Europe and Asia. HIV-2
reverse transcriptase (RT) demonstrates an intrinsic resistance to
non-nucleoside RT inhibitors (NNRTIs), one of two classes of anti-AIDS drugs
that target the viral RT. We report the crystal structure of HIV-2 RT to 2.35 A
resolution, which reveals molecular details of the resistance to NNRTIs. HIV-2
RT has a similar overall fold to HIV-1 RT but has structural differences within
the "NNRTI pocket" at both conserved and nonconserved residues. The
structure points to the role of sequence differences that can give rise to
unfavorable inhibitor contacts or destabilization of part of the binding pocket
at positions 101, 106, 138, 181, 188, and 190. We also present evidence that the
conformation of Ile-181 compared with the HIV-1 Tyr-181 could be a significant
contributory factor to this inherent drug resistance of HIV-2 to NNRTIs. The
availability of a refined structure of HIV-2 RT will provide a stimulus for the
structure-based design of novel non-nucleoside inhibitors that could be used
against HIV-2 infection.
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Figure 2.
Fig 2. (A) Stereo diagram comparing the NNRTI site of an
unliganded HIV-1 RT and the corresponding region of HIV-2 RT.
The HIV-1 RT is colored in gray, and the main chain and side
chains of HIV-2 RT are shown in green and orange, respectively.
(B) Stereo diagram showing part of the HIV-2 RT p55 subunit
containing the Ile-181 and Leu-188 side chains (blue and green)
overlapped with the corresponding region of the p66 subunit in
the nevirapine-bound HIV-1 RT (orange and red). Nevirapine is
drawn as ball-and-sticks and colored by atoms. (C) Stereo
diagram showing a cavity located at the junction of the p68
palm, p68 connection, and p55 fingers domains (ribbon and coils
colored in green, red, and blue, respectively). Side chains of
the residues lining the cavity, a bound glycerol and a sulfate
are shown in ball-and-stick representation, and are colored by
atoms, with carbon atoms in cyan for the side chains and black
for the glycerol. Water molecules in the cavity are shown as
small red spheres. Larger red spheres label the C  position
of the three catalytic Asp residues at the polymerase active
site. Nevirapine colored in gray is shown to mark the NNRTI site
in HIV-1 RT. The dashed yellow sticks indicate the four H-bonds
from the glycerol to the carbonyl oxygen of Gly-99, the
main-chain nitrogen of Ala-101, and a water molecule.
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Figure 3.
Fig 3. Comparison of the structure around residues 181 and
188 of the p55 subunit in HIV-2 RT with that of p51 subunit in
HIV-1 RT. The main chains are shown as ribbons and coils, and
side chains as ball-and-stick representations, with HIV-1 RT
colored orange and red, and HIV-2 RT blue and green.
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Secondary reference #1
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Title
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Cloning, Expression, Purification, And crystallisation of HIV-2 reverse transcriptase.
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Authors
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L.E.Bird,
P.P.Chamberlain,
G.B.Stewart-Jones,
J.Ren,
D.I.Stuart,
D.K.Stammers.
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Ref.
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Protein Expr Purif, 2003,
27,
12-18.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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