|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Hiv-1 reverse transcriptase complex with DNA and nevirapine reveals non-Nucleoside inhibition mechanism.
|
|
|
Authors
|
|
K.Das,
S.E.Martinez,
J.D.Bauman,
E.Arnold.
|
|
|
Ref.
|
|
Nat Struct Biol, 2012,
19,
253-259.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
No abstract given.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Structural basis for the role of the k65r mutation in HIV-1 reverse transcriptase polymerization, Excision antagonism, And tenofovir resistance.
|
|
|
Authors
|
|
K.Das,
R.P.Bandwar,
K.L.White,
J.Y.Feng,
S.G.Sarafianos,
S.Tuske,
X.Tu,
A.D.Clark,
P.L.Boyer,
X.Hou,
B.L.Gaffney,
R.A.Jones,
M.D.Miller,
S.H.Hughes,
E.Arnold.
|
|
|
Ref.
|
|
J Biol Chem, 2009,
284,
35092-35100.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
Chemical structures of dATP, TFV-DP, AZT-TP, and 3TC-TP.
|
|
Figure 4.
Three distinct mechanisms of NRTI resistance through
mutations at three distinct sites. Superposition of
excision-enhancing mutation or TAM (M41L, D67N, K70R, T215Y, and
K219Q) RT·dsDNA·AZTppppA structure^4 on K65R
RT·dsDNA·dATP structure at their dNTP-binding
sites; AZTppppA is the product of AZT monophosphate by
ATP-mediated excision. Although the two structures contained two
distinct sites of mutations and crystallized in two distinct
space groups, they superimpose very well at the active site
region. The mutated residues Arg^70 and Tyr^215 are from the
crystal structure of excision-enhancing mutation RT complex,
whereas M184V was modeled based on the structure of the M184V
RT·dsDNA binary complex (49). The surfaces of the
K65R/Arg^72 platform (gray mesh) and M184V (3TC resistance
mutation site; magenta mesh) form two walls on either side of
the ribose ring, whereas the other end of the K65R/Arg^72
platform interfaces with K70R, a primary mutation site for AZT
resistance.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
which is an Open Access publication published by the ASBMB
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Structural basis of HIV-1 resistance to azt by excision.
|
|
|
Authors
|
|
X.Tu,
K.Das,
Q.Han,
J.D.Bauman,
A.D.Clark,
X.Hou,
Y.V.Frenkel,
B.L.Gaffney,
R.A.Jones,
P.L.Boyer,
S.H.Hughes,
S.G.Sarafianos,
E.Arnold.
|
|
|
Ref.
|
|
Nat Struct Biol, 2010,
17,
1202-1209.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #3
|
|
|
Title
|
|
High-Resolution structures of HIV-1 reverse transcriptase/tmc278 complexes: strategic flexibility explains potency against resistance mutations.
|
|
|
Authors
|
|
K.Das,
J.D.Bauman,
A.D.Clark,
Y.V.Frenkel,
P.J.Lewi,
A.J.Shatkin,
S.H.Hughes,
E.Arnold.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2008,
105,
1466-1471.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 2.
Binding mode of TMC278 to HIV-1 RT. (A) Interactions of
TMC278 (gray) with NNRTI-binding pocket residues (in yellow).
(B) The molecular surface (orange) defines the hydrophobic
tunnel that accommodates the cyanovinyl group of TMC278.
|
|
Figure 4.
Comparison of L100I/K103N mutant RT (orange side
chains)/TMC278 (cyan) structure with the wild-type RT (yellow
side chains)/TMC278 (gray) structures reveals wiggling (A) and
jiggling (B) of TMC278.
|
|
|
|
|
|
Secondary reference #4
|
|
|
Title
|
|
Roles of conformational and positional adaptability in structure-Based design of tmc125-R165335 (etravirine) and related non-Nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-Type and drug-Resistant HIV-1 variants.
|
|
|
Authors
|
|
K.Das,
A.D.Clark,
P.J.Lewi,
J.Heeres,
M.R.De jonge,
L.M.Koymans,
H.M.Vinkers,
F.Daeyaert,
D.W.Ludovici,
M.J.Kukla,
B.De corte,
R.W.Kavash,
C.Y.Ho,
H.Ye,
M.A.Lichtenstein,
K.Andries,
R.Pauwels,
M.P.De béthune,
P.L.Boyer,
P.Clark,
S.H.Hughes,
P.A.Janssen,
E.Arnold.
|
|
|
Ref.
|
|
J Med Chem, 2004,
47,
2550-2560.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #5
|
|
|
Title
|
|
Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance.
|
|
|
Authors
|
|
H.Huang,
R.Chopra,
G.L.Verdine,
S.C.Harrison.
|
|
|
Ref.
|
|
Science, 1998,
282,
1669-1675.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. RT-DNA tethering reaction. Chemistry of disulfide
bond formation between the side chain of an engineered cysteine
residue (blue) in helix H (gold) of RT to a thiol group in the
minor groove of DNA (activated as the mixed disulfide), which is
tethered to N2 of a dG (green) in the template:primer.
|
|
Figure 6.
Fig. 6. Sites of mutations conferring resistance to various
nucleoside analog drugs. (A) "Front" view, corresponding to the
orientation in Fig. 4. The polypeptide backbone of the fingers
and palm domains (residues 1 to 235) is shown as a red worm, and
locations of resistance mutations are indicated by colored
squares. The substrates are shown in Corey-Pauling-Koltun
representation, with colors as in Fig. 3. The color code for
mutations is as follows: light blue for resistance to ddI, ddC,
and 3TC; blue for resistance to AZT; and violet for cross
resistance to AZT and ddI or ddC. The location of the NNRTI
binding site is shown by an arrow. Side chains of the residues
at which mutations affect dideoxynucleotide sensitivity project
forward: L74 bears on the templating base, and V at this
position will also shift Q151 and R72 and hence the dNTP itself;
M184 contacts the backbone and base at the primer terminus, and
mutation to I or V will also generate a contact to the sugar
ring of the dNTP; K65 contacts the  -phosphate;
and T69D (resistance to ddC) can probably best be explained by
assuming a conformational effect on the fingers loop,
transmitted to the dNTP by contacts from other fingers residues.
(B) "Back" view, from the direction opposite to the one in (A).
Side chains of AZT resistance mutations project toward this
surface. One of the earliest mutations that appears in patients
on AZT monotherapy is K70R. The Lys70 residue projects directly
outward in the current model, but mutation to arginine (with
five hydrogen-bond donors in fixed orientations on the
guanidinium group) could readily induce side-chain
reorientation, with contacts to Asp113 or the -phosphate.
Subsequent appearance of T215Y/F confers higher levels of
resistance. This mutation, likely to affect the rear of the 3'
pocket, is frequently "tuned" by appearance of others: K210W
(which probably stabilizes the alteration at 215), M41L, and
D67N and K219Q (which likely affect the interaction of fingers
and palm and hence the formation of the 3' pocket during the
polymerization cycle) (16). Figure 4A was prepared with GRASP
(50), and Figs. 3, 4B, 5, and 6, with RIBBONS (51).
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from the AAAs
|
|
|
|
|
|
