Science,
Год журнала:
2024,
Номер
386(6721), С. 551 - 560
Опубликована: Окт. 31, 2024
The
spliceosome
is
the
complex
molecular
machinery
that
sequentially
assembles
on
eukaryotic
messenger
RNA
precursors
to
remove
introns
(pre-mRNA
splicing),
a
physiologically
regulated
process
altered
in
numerous
pathologies.
We
report
transcriptome-wide
analyses
upon
systematic
knock
down
of
305
components
and
regulators
human
cancer
cells
reconstruction
functional
splicing
factor
networks
govern
different
classes
alternative
decisions.
results
disentangle
intricate
circuits
cross-regulation,
reveal
precise
architecture
late-assembling
U4/U6.U5
tri-small
nuclear
ribonucleoprotein
(snRNP)
complexes
regulates
splice
site
pairing,
discover
an
unprecedented
division
labor
among
protein
U1
snRNP
for
regulating
exon
definition
5'
selection.
Thus,
we
provide
resource
explore
physiological
pathological
mechanisms
regulation.
Advances
in
computational
tools
for
atomic
model
building
are
leading
to
accurate
models
of
large
molecular
assemblies
seen
electron
microscopy,
often
at
challenging
resolutions
3-4
Å.
We
describe
new
methods
the
UCSF
ChimeraX
modeling
package
that
take
advantage
machine-learning
structure
predictions,
provide
likelihood-based
fitting
maps,
and
compute
per-residue
scores
identify
errors.
Additional
model-building
assist
analysis
mutations,
post-translational
modifications,
interactions
with
ligands.
present
latest
capabilities,
including
several
community-developed
extensions.
is
available
free
charge
noncommercial
use
https://www.rbvi.ucsf.edu/chimerax.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 26, 2024
Abstract
Structure-based
generative
chemistry
is
essential
in
computer-aided
drug
discovery
by
exploring
a
vast
chemical
space
to
design
ligands
with
high
binding
affinity
for
targets.
However,
traditional
silico
methods
are
limited
computational
inefficiency,
while
machine
learning
approaches
face
bottlenecks
due
auto-regressive
sampling.
To
address
these
concerns,
we
have
developed
conditional
deep
model,
PMDM,
3D
molecule
generation
fitting
specified
PMDM
consists
of
equivariant
diffusion
model
both
local
and
global
molecular
dynamics,
enabling
consider
the
conditioned
protein
information
generate
molecules
efficiently.
The
comprehensive
experiments
indicate
that
outperforms
baseline
models
across
multiple
evaluation
metrics.
evaluate
applications
under
real
scenarios,
conduct
lead
compound
optimization
SARS-CoV-2
main
protease
(M
pro
)
Cyclin-dependent
Kinase
2
(CDK2),
respectively.
selected
synthesized
evaluated
their
in-vitro
activities
against
CDK2,
displaying
improved
CDK2
activity.
Nature,
Год журнала:
2024,
Номер
631(8019), С. 232 - 239
Опубликована: Май 29, 2024
Mitochondria
play
a
pivotal
part
in
ATP
energy
production
through
oxidative
phosphorylation,
which
occurs
within
the
inner
membrane
series
of
respiratory
complexes
Frontiers in Immunology,
Год журнала:
2024,
Номер
15
Опубликована: Июнь 14, 2024
C-reactive
protein
(CRP)
is
a
plasma
that
evolutionarily
conserved,
found
in
both
vertebrates
and
many
invertebrates.
It
member
of
the
pentraxin
superfamily,
characterized
by
its
pentameric
structure
calcium-dependent
binding
to
ligands
like
phosphocholine
(PC).
In
humans
various
other
species,
concentration
this
markedly
elevated
during
inflammatory
conditions,
establishing
it
as
prototypical
acute
phase
plays
role
innate
immune
responses.
This
feature
can
also
be
used
clinically
evaluate
severity
inflammation
organism.
Human
CRP
(huCRP)
exhibit
contrasting
biological
functions
due
conformational
transitions,
while
species
retains
conserved
protective
vivo
.
The
focus
review
will
on
structural
traits
CRP,
regulation
expression,
activate
complement,
function
related
diseases
The Journal of Physical Chemistry B,
Год журнала:
2024,
Номер
128(41), С. 9976 - 10042
Опубликована: Сен. 20, 2024
Since
its
inception
nearly
a
half
century
ago,
CHARMM
has
been
playing
central
role
in
computational
biochemistry
and
biophysics.
Commensurate
with
the
developments
experimental
research
advances
computer
hardware,
range
of
methods
applicability
have
also
grown.
This
review
summarizes
major
that
occurred
after
2009
when
last
was
published.
They
include
following:
new
faster
simulation
engines,
accessible
user
interfaces
for
convenient
workflows,
vast
array
analysis
encompass
quantum
mechanical,
atomistic,
coarse-grained
levels,
as
well
extensive
coverage
force
fields.
In
addition
to
providing
current
snapshot
development,
this
may
serve
starting
point
exploring
relevant
theories
tackling
contemporary
emerging
problems
biomolecular
systems.
is
freely
available
academic
nonprofit
at
https://academiccharmm.org/program.
Journal of Molecular Biology,
Год журнала:
2024,
Номер
436(17), С. 168656 - 168656
Опубликована: Июнь 19, 2024
Crosslinking
mass
spectrometry
(MS)
has
emerged
as
an
important
technique
for
elucidating
the
in-solution
structures
of
protein
complexes
and
topology
protein-protein
interaction
networks.
However,
expanding
user
community
lacked
integrated
visualisation
tool
that
helped
them
make
use
crosslinking
data
investigating
biological
mechanisms.
We
addressed
this
need
by
developing
xiVIEW,
a
web-based
application
designed
to
streamline
MS
analysis,
which
we
present
here.
xiVIEW
provides
user-friendly
interface
accessing
coordinated
views
spectrometric
data,
network
visualisation,
annotations
extracted
from
trusted
repositories
like
UniProtKB,
available
3D
structures.
In
accordance
with
recent
recommendations
community,
(i)
standards
compliant
parser
improve
integration
(ii)
offers
accessible
tools.
By
promoting
adoption
standard
file
formats
providing
comprehensive
platform,
empowers
both
experimentalists
modellers
alike
pursue
their
respective
research
interests.
anticipate
will
advance
MS-inspired
research,
facilitate
broader
more
effective
investigations
into
complex
systems.
Nucleic Acids Research,
Год журнала:
2024,
Номер
52(W1), С. W318 - W323
Опубликована: Апрель 18, 2024
Abstract
The
‘structure
assessment’
web
server
is
a
one-stop
shop
for
interactive
evaluation
and
benchmarking
of
structural
models
macromolecular
complexes
including
proteins
nucleic
acids.
A
user-friendly
dashboard
links
sequence
with
structure
information
results
from
variety
state-of-the-art
tools,
which
facilitates
the
visual
exploration
models.
integrates
stereochemistry
information,
secondary
global
local
model
quality
assessment
tertiary
comparative
protein
models,
as
well
prediction
membrane
location.
In
addition,
mode
available
where
can
be
compared
to
reference
structure,
providing
easy
access
scores
that
have
been
used
in
recent
CASP
experiments
CAMEO.
at
https://swissmodel.expasy.org/assess.
Nature Structural & Molecular Biology,
Год журнала:
2024,
Номер
31(7), С. 1134 - 1144
Опубликована: Апрель 12, 2024
Microtubule
(MT)
filaments,
composed
of
α/β-tubulin
dimers,
are
fundamental
to
cellular
architecture,
function
and
organismal
development.
They
nucleated
from
MT
organizing
centers
by
the
evolutionarily
conserved
γ-tubulin
ring
complex
(γTuRC).
However,
molecular
mechanism
nucleation
remains
elusive.
Here
we
used
cryo-electron
tomography
determine
structure
native
γTuRC
capping
minus
end
a
in
context
enriched
budding
yeast
spindles.
In
our
structure,
presents
subunits
seed
exclusively
13-protofilament
MTs,
adopting
an
active
closed
conformation
as
perfect
geometric
template
for
nucleation.
Our
reconstruction
revealed
that
coiled-coil
protein
staples
first
row
alternating
positions
along
γTuRC.
This
positioning
onto
suggests
role
augmenting
γTuRC-mediated
Based
on
results,
describe
model
activation
The
synaptonemal
complex
(SC)
is
a
zipper-like
protein
assembly
that
links
homologous
chromosomes
to
regulate
recombination
and
segregation
during
meiosis.
SC
has
been
notoriously
refractory
in
vitro
reconstitution,
thus
leaving
its
molecular
organization
largely
unknown.
Here,
we
report
moonlighting
function
of
two
paralogous
S-phase
kinase-associated
1
(Skp1)-related
proteins
(SKR-1
SKR-2),
well-known
adaptors
the
Skp1-Cul1-F-box
(SCF)
ubiquitin
ligase,
as
key
missing
components
