 |
PDBsum entry 1sdt
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structures of HIV protease V82a and l90m mutants reveal changes in the indinavir-Binding site.
|
|
|
Authors
|
|
B.Mahalingam,
Y.F.Wang,
P.I.Boross,
J.Tozser,
J.M.Louis,
R.W.Harrison,
I.T.Weber.
|
|
|
Ref.
|
|
Eur J Biochem, 2004,
271,
1516-1524.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The crystal structures of the wild-type HIV-1 protease (PR) and the two
resistant variants, PR(V82A) and PR(L90M), have been determined in complex with
the antiviral drug, indinavir, to gain insight into the molecular basis of drug
resistance. V82A and L90M correspond to an active site mutation and nonactive
site mutation, respectively. The inhibition (K(i)) of PR(V82A) and PR(L90M) was
3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only
a modest decrease, of 10-15%, in their k(cat)/K(m) values relative to PR. The
crystal structures were refined to resolutions of 1.25-1.4 A to reveal critical
features associated with inhibitor resistance. PR(V82A) showed local changes in
residues 81-82 at the site of the mutation, while PR(L90M) showed local changes
near Met90 and an additional interaction with indinavir. These structural
differences concur with the kinetic data.
|
|
|
|
|
|
|
|
Figure 3.
Fig. 3. Interaction of Met90'and Asp25' in PR[L90M]. (A)
The 2Fo–Fc electron density map showing Met90', Asp25' and
Thr26'in the PR[L90M] structure. The side chain of Met90' has
two conformations, and one conformation has a short separation
from the carbonyl oxygen of the catalytic Asp25'. (B) Comparison
of Met90' in PR[L90M] and Leu90' in the wild-type HIV-1 protease
(PR) relative to Asp25'. The PR residues are in black and the
PR[L90M] residues are in gray. Hydrogen bonds are indicated by
dashed lines, with the distances shown in Å.
|
|
Figure 6.
Fig. 6. Structural variation in residues 81–82 near
indinavir. Stereoview showing the benzyl group of indinavir
interacting with residues 81–82, using the major conformation
of Val82. The wild-type HIV-1 protease (PR) structure is in
black and the mutant is in gray bonds. Interatomic distances are
given in Å. (A) PR[V82A] superimposed on PR. (B) PR[L90M]
superimposed on PR.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the Federation of European Biochemical Societies:
Eur J Biochem
(2004,
271,
1516-1524)
copyright 2004.
|
|
|
|
|
|
|
