bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 23, 2024
Abstract
Molecular
glues
represent
an
innovative
class
of
drugs
that
enable
previously
impossible
protein-protein
interactions,
but
their
rational
design
remains
challenging,
a
problem
accurate
ternary
complex
modeling
can
significantly
address.
Here
we
present
YDS-Ternoplex,
novel
computational
approach
enhances
AlphaFold
3-type
models
by
incorporating
enhanced
sampling
inductive
bias
during
inference
to
accurately
predict
molecular
glue-mediated
structures.
We
demonstrate
YDS-Ternoplex’s
capabilities
across
five
diverse
test
cases,
including
both
E3
ligase-based
systems
(VHL:CDO1
and
CRBN
complexes
with
mTOR-FRB,
NEK7,
VAV1-SH3c)
non-E3
ligase
(FKBP12:mTOR-FRB).
The
model
achieves
remarkable
accuracy
RMSD
values
as
low
1.303
Å
compared
experimental
structures
successfully
predicts
interfaces
not
in
training
data.
Notably,
the
FKBP12:mTOR-FRB
case,
YDS-Ternoplex
correctly
interface
configuration
instead
defaulting
known
interactions
data,
demonstrating
strong
generalization
capabilities.
Our
results
suggest
strategic
enhancement
process
through
improve
prediction
accuracy,
potentially
accelerating
development
glue
therapeutics
for
undruggable
targets.
MedComm,
Journal Year:
2024,
Volume and Issue:
5(10)
Published: Oct. 1, 2024
Melanoma's
high
metastatic
potential,
especially
to
the
brain,
poses
significant
challenges
patient
survival.
The
blood‒brain
barrier
(BBB)
is
a
major
obstacle
effective
treatment
of
melanoma
brain
metastases.
We
screened
antipsychotic
drugs
capable
crossing
BBB
and
identified
penfluridol
(PF)
as
most
active
candidate.
PF
reduced
cell
viability
induced
apoptosis.
In
animal
models,
effectively
inhibited
growth
metastasis
lung
brain.
Using
immunoprecipitation
combined
with
high-resolution
mass
spectrometry,
other
techniques
such
drug
affinity
responsive
target
stability,
we
CIP2A
direct
binding
protein
PF.
highly
expressed
in
its
metastases,
linked
poor
prognosis.
can
restore
Protein
Phosphatase
2A
activity
by
promoting
degradation,
thereby
inhibiting
several
key
oncogenic
pathways,
including
AKT
c-Myc.
Additionally,
von
Hippel‒Lindau
(VHL)
endogenous
E3
ligase
for
CIP2A,
enhances
interaction
between
VHL
ubiquitin‒proteasome
degradation
metastasis.
Overall,
this
study
not
only
suggests
PF's
potential
treating
metastases
but
also
highlights
therapeutic
strategy
melanoma.
ACS Chemical Biology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 4, 2024
Target
protein
degradation
(TPD)
is
a
promising
strategy
for
catalytic
downregulation
of
target
proteins
through
various
cellular
proteolytic
pathways.
Despite
numerous
reports
on
novel
TPD
mechanisms,
the
discovery
target-specific
ligands
remains
major
challenge.
Unlike
small-molecule
ligands,
aptamers
offer
significant
advantages,
owing
to
their
SELEX-based
systematic
screening
method.
To
fully
utilize
TPD,
we
designed
an
aptamer
and
N-degron
ensemble
system
(AptaGron)
that
circumvents
need
synthetic
conjugations
between
proteolysis-recruiting
units.
In
our
AptaGron
system,
peptide
nucleic
acid
containing
sequence
complementary
was
designed.
Using
this
successfully
degraded
three
proteins,
tau,
nucleolin,
eukaryotic
initiation
factor
4E
(eIF4E),
which
lack
specific
ligands.
Our
results
highlight
potential
approach
as
robust
platform
targeted
degradation.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 22, 2024
Abstract
Leucine-rich
repeat
kinase
2
(LRRK2)
is
a
central
player
in
cellular
signaling
and
significant
contributor
to
Parkinson’s
disease
(PD)
pathogenesis.
14-3-3
proteins
are
essential
regulators
of
LRRK2,
modulating
its
activity.
Here,
we
present
the
cryo-
electron
microscopy
structure
LRRK2:14-3-3
autoinhibitory
complex,
showing
that
dimer
stabilizes
an
autoinhibited
LRRK2
monomer
by
binding
key
phosphorylation
sites
COR-A
COR-B
subdomains
within
Roc-COR
GTPase
domain
LRRK2.
This
interaction
locks
inactive
conformation,
restricting
LRR
mobility
preventing
dimerization
oligomer
formation.
Our
mutagenesis
studies
reveal
PD-associated
mutations
at
COR:14-3-3
interface
reduce
binding,
diminishing
inhibitory
effect
on
These
findings
provide
structural
basis
for
understanding
how
likely
remains
dormant
cells,
illuminate
aspects
critical
PD
biomarkers,
suggest
therapeutic
strategies
enhance
LRRK2-14-3-3
interactions
treat
related
disorders.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 23, 2024
Abstract
Molecular
glues
represent
an
innovative
class
of
drugs
that
enable
previously
impossible
protein-protein
interactions,
but
their
rational
design
remains
challenging,
a
problem
accurate
ternary
complex
modeling
can
significantly
address.
Here
we
present
YDS-Ternoplex,
novel
computational
approach
enhances
AlphaFold
3-type
models
by
incorporating
enhanced
sampling
inductive
bias
during
inference
to
accurately
predict
molecular
glue-mediated
structures.
We
demonstrate
YDS-Ternoplex’s
capabilities
across
five
diverse
test
cases,
including
both
E3
ligase-based
systems
(VHL:CDO1
and
CRBN
complexes
with
mTOR-FRB,
NEK7,
VAV1-SH3c)
non-E3
ligase
(FKBP12:mTOR-FRB).
The
model
achieves
remarkable
accuracy
RMSD
values
as
low
1.303
Å
compared
experimental
structures
successfully
predicts
interfaces
not
in
training
data.
Notably,
the
FKBP12:mTOR-FRB
case,
YDS-Ternoplex
correctly
interface
configuration
instead
defaulting
known
interactions
data,
demonstrating
strong
generalization
capabilities.
Our
results
suggest
strategic
enhancement
process
through
improve
prediction
accuracy,
potentially
accelerating
development
glue
therapeutics
for
undruggable
targets.
