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How Viagra works,
structurally
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Anti-impotence drugs like sildenafil (Viagra, shown) work by binding with an enzyme known as PDE5, a member
of the enzyme superfamily of phosphodiesterases.
PDE5 thwarts erections by breaking down cyclic guanosine
monophosphate (cGMP)
needed for smooth-muscle relaxation. Drug designers have therefore looked
for molecules like sildenafil that are
structurally similar to cGMP. An even better
tool, however, would be a detailed picture of PDE5 itself bound with an
inhibitor. Now, a team led by Joong Myung Cho of CrystalGenomics,
in Daejeon, South Korea, has determined crystal
structures of human PDE5 complexed with each of
three different inhibitors: sildenafil, tadalafil, and vardenafil [Nature,
425, 98 (2003)]. The topology of these structures is similar to that
of an already-studied system involving the related PDE4 and an inhibitor,
but only 23% of the amino acid sequences in the enzymes' catalytic regions
are shared. This information should help researchers design better, more
specific drugs that inhibit PDE5, the authors say.
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Fluorescence of lone nanotubes
Until now, to study the optical properties of single-walled carbon nanotubes
(SWNTs), researchers have had to use ensembles of
the molecules. However, a team of researchers from the Institute of Optics and the
chemistry department at the University
of Rochester has found that unavoidable inhomogeneities
in these ensembles may lead scientists to miss important nanotube characteristics. In the first report of
fluorescence from individual carbon nanotubes [Science,
301, 1354 (2003)], the team, led by professors Todd D. Krauss and
Lukas Novotny, found that nanotubes with
identical structures emit with different frequencies, line widths, and
intensities--probably due to defects or the local environment. Also, the
researchers unexpectedly found that, unlike most other molecules, SWNT
fluorescence does not fluctuate. Krauss says these results could lead to
future applications in nanophotonics.
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Ionomics probes effects of genes on ions
A new genomics-related field has just been conceived. Called "ionomics," it's the study of how genes regulate
levels of single-element ions in cells [Nat. Biotechnol.,
published online Aug. 31, http://dx.doi.org/10.1038/nbt865].
The ionomics concept was devised by a team led by
associate professor David E. Salt of Purdue
University--whose surname suggests he might indeed know a thing or two
about ions. Others have studied gene networks that control mineral ions,
but Salt and coworkers believe the field deserves more systematic
attention. In the study, the team generated random mutations in Arabidopsis
thaliana (wall cress) and found that 2 to 4% of the plant's genome
regulates the plant's "ionome"--defined
as 18 ions that play a key role in its nutrition. Mapping ion-regulating
genes could aid phytoremediation of pollutant
trace elements and lead to the engineering of crop plants with enhanced
nutritional value. Salt is currently collaborating with NuCycle
Therapy, Hillside, N.J., to develop plants enriched in selenium.
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<
span style='font-size:13.5pt;
color:black'>Presenilin-1's second role in Alzheimer's
Presenilin-1 (PS-1) is a protein best known for its involvement in cleavage of the amyloid precursor protein, a step that can lead to
formation of the brain plaques typical of Alzheimer's disease. Now, a team
headed by Nikolaos K. Robakis,
a professor in the psychiatry department and in the Center for Neurobiology at Mount Sinai
School of Medicine, New York City, has shown that PS-1 has another
function [Cell, 114, 635 (2003)]. PS-1 promotes cleavage of
neural cadherin (N-cadherin),
producing compounds such as N-Cad/CTF2 that are necessary for proper
brain-cell function and probably for memory formation. Mutations in the
genes that encode PS-1 are associated with many of the early-onset cases of
inherited Alzheimer's disease. The researchers show that these mutations
lead to the production of PS-1 that is less capable than normal PS-1 of cleaving
N-cadherin. That cuts production of N-Cad/CTF2, a
compound that promotes degradation of the transcriptional coactivator CBP. Increased CBP concentrations may then
damage neurons and synapses, the researchers suggest. They propose that
some Alzheimer's cases could be treated with drugs designed to deliver or
increase production of N-Cad/CTF2.
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Electron counting rules keep adding up
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The octet rule, 18-electron
rule, and 4n + 2 H¸ckel rule are well-known
electron-counting methods used to predict stable structures of compounds.
There's also the Wade-Mingos n + 1 rule
for counting skeletal-bonding electron pairs in boranes
and Jemmis' mno
rule for condensed boranes and metallocenes, both of which have been used to predict
new compounds. Chemistry professor Paul v. R. Schleyer
and postdoc Zhi-Xiang Wang
of the University of Georgia, Athens, have now developed a 6m + 2n
rule to predict a new class of boranes and carboranes in which the polyhedral cage structures with
protruding hydrogen atoms resemble spiny sea urchins [J.
Am. Chem. Soc., 125, 10484 (2003)]. The number of skeletal
electrons needed for the hypothetical compounds, built up by replacing
carbon with boron, is derived from the number of m faces larger than triangles
and n triangles. The rule shows that only certain combinations of CH and BH
groups will lead to stable compounds not predicted by the n + 1
rule, such as C4B14H18 (m = 6, n
= 2) and B92H928!= (shown; m = 32, n
= 0). The latter is derived from C60 and includes additional
boron caps for each face. The researchers expect the "sea
urchins" will quickly become targets for synthetic borane
chemists.
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