 |
PDBsum entry 6fiv
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
6fiv
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural studies of fiv and HIV-1 proteases complexed with an efficient inhibitor of fiv protease.
|
|
|
Authors
|
|
M.Li,
G.M.Morris,
T.Lee,
G.S.Laco,
C.H.Wong,
A.J.Olson,
J.H.Elder,
A.Wlodawer,
A.Gustchina.
|
|
|
Ref.
|
|
Proteins, 2000,
38,
29-40.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Three forms of feline immunodeficiency virus protease (FIV PR), the wild type
(wt) and two single point mutants, V59I and Q99V, as well as human
immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the
C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace
residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR
residues at the structurally equivalent position. TL-3 shows decreased
(improved) inhibition constants with these FIV PR mutants relative to wt FIV PR.
Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'),
small differences are evident in the conformation of the Phe side chains of TL-3
at the P1 and P1' positions in the complexes with the mutated FIV PRs. The
differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a
significant improvement in the inhibition constants of TL-3 with the two mutant
FIV PRs. Large differences between the HIV-1 and FIV PR complexes are evident in
the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1
PR:TL-3, these groups bind over the flap region, whereas in the FIV PR
complexes, the rings are located along the major axis of the active site. A
significant difference in the location of the flaps in this region of the HIV-1
and FIV PRs correlates with the observed conformational changes in the binding
mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings
provide a structural explanation of the observed Ki values for TL-3 with the
different PRs and will further assist in the development of improved inhibitors.
|
|
|
|
|
|
|
|
Figure 4.
Figure 4. Superposition of the crystal structures of wt FIV PR
(blue) and its two mutants, V59I (yellow) and Q99V (purple),
complexed with TL-3, near the S1 binding site. Water molecules
are shown as spheres, whereas hydrogen bonds are shown as dotted
lines.
|
|
Figure 6.
Figure 6. Comparison of the interface between the flap region
and loop 93-98 (76-81) in wt FIV PR (blue) and HIV-1 PR (pink).
|
|
|
|
|
|
The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2000,
38,
29-40)
copyright 2000.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Structure of an inhibitor complex of the proteinase from feline immunodeficiency virus.
|
|
|
Authors
|
|
A.Wlodawer,
A.Gustchina,
L.Reshetnikova,
J.Lubkowski,
A.Zdanov,
K.Y.Hui,
E.L.Angleton,
W.G.Farmerie,
M.M.Goodenow,
D.Bhatt.
|
|
|
Ref.
|
|
Nat Struct Biol, 1995,
2,
480-488.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
