3 research outputs found
Room Temperature Neutron Crystallography of Drug Resistant HIVâ1 Protease Uncovers Limitations of Xâray Structural Analysis at 100 K
HIV-1 protease inhibitors are crucial
for treatment of HIV-1/AIDS,
but their effectiveness is thwarted by rapid emergence of drug resistance.
To better understand binding of clinical inhibitors to resistant HIV-1
protease, we used room-temperature joint X-ray/neutron (XN) crystallography
to obtain an atomic-resolution structure of the protease triple mutant
(V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals
a D<sup>+</sup> ion located midway between the inner OÎŽ1 oxygen
atoms of the catalytic aspartic acid residues. Comparison of the current
XN structure with our previous XN structure of the wild-type HIV-1
protease-amprenavir complex suggests that the three mutations do not
significantly alter the drugâenzyme interactions. This is in
contrast to the observations in previous 100 K X-ray structures of
these complexes that indicated loss of interactions by the drug with
the triple mutant protease. These findings, thus, uncover limitations
of structural analysis of drug binding using X-ray structures obtained
at 100 K
Joint Xâray/Neutron Crystallographic Study of HIVâ1 Protease with Clinical Inhibitor Amprenavir: Insights for Drug Design
HIV-1
protease is an important target for the development of antiviral
inhibitors to treat AIDS. A room-temperature joint X-ray/neutron structure
of the protease in complex with clinical drug amprenavir has been
determined at 2.0 Ă
resolution. The structure provides direct
determination of hydrogen atom positions in the enzyme active site.
Analysis of the enzymeâdrug interactions suggests that some
hydrogen bonds may be weaker than deduced from the non-hydrogen interatomic
distances. This information may be valuable for the design of improved
protease inhibitors
Systematic and Controllable Negative, Zero, and Positive Thermal Expansion in Cubic Zr<sub>1â<i>x</i></sub>Sn<sub><i>x</i></sub>Mo<sub>2</sub>O<sub>8</sub>
We
describe the synthesis and characterization of a family of materials,
Zr<sub>1â<i>x</i></sub>Sn<sub><i>x</i></sub>Mo<sub>2</sub>O<sub>8</sub> (0 < <i>x</i> < 1), whose
isotropic thermal expansion coefficient can be systematically varied
from negative to zero to positive values. These materials allow tunable
expansion in a single phase as opposed to using a composite system.
Linear thermal expansion coefficients, α<sub>l</sub>, ranging
from â7.9(2) Ă 10<sup>â6</sup> to +5.9(2) Ă
10<sup>â6</sup> K<sup>â1</sup> (12â500 K) can
be achieved across the series; contraction and expansion limits are
of the same order of magnitude as the expansion of typical ceramics.
We also report the various structures and thermal expansion of âcubicâ
SnMo<sub>2</sub>O<sub>8</sub>, and we use time- and temperature-dependent
diffraction studies to describe a series of phase transitions between
different ordered and disordered states of this material