bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 12, 2024
Abstract
The
glucocorticoid
receptor
(GR)
is
a
leading
drug
target
due
to
its
anti-inflammatory
and
immunosuppressive
roles.
functional
oligomeric
conformation
of
full-length
GR
(FL-GR),
which
key
for
biological
activity,
remains
disputed.
Here
we
present
new
crystal
structure
agonist-bound
ligand-binding
domain
(GR-LBD)
comprising
eight
copies
non-canonical
dimer.
relevance
this
dimer
multimerization
in
living
cells
has
been
verified
by
studying
single-and
double-point
mutants
FL-GR
fluorescence
microscopy
(Number
&
Brightness)
transcriptomic
analysis.
Self-association
GR-LBD
basic
two
mutually
exclusive
assemblies
reveals
clues
activity
cells.
We
propose
model
the
multidomain
based
on
our
data
suggest
detailed
oligomerization
pathway.
This
reconciles
all
currently
available
structural
information
provides
more
comprehensive
understanding
rare
resistance
disorder
(Chrousos
syndrome).
Current Opinion in Cell Biology,
Год журнала:
2025,
Номер
95, С. 102527 - 102527
Опубликована: Май 16, 2025
This
review
explores
recent
emerging
insights
into
enhancer
action,
focusing
on
underexplored
aspects
such
as
the
physical
size
of
regulatory
elements,
stochasticity
transcription
factor
binding
and
chromatin
structure,
role
nonlinear
processes
in
reconciling
longstanding
discrepancies
between
theoretical
models
experimental
observations.
Together,
these
provide
a
nuanced
view
biology,
highlighting
complexity
gene
regulation
need
for
innovative
methodologies
to
further
decode
mechanisms.
Nucleic Acids Research,
Год журнала:
2025,
Номер
53(9)
Опубликована: Май 10, 2025
Abstract
While
the
cohesin
complex
is
a
key
player
in
genome
architecture,
how
it
localizes
to
specific
chromatin
sites
not
understood.
Recently,
we
and
others
have
proposed
that
direct
interactions
with
transcription
factors
lead
localization
of
cohesin-loader
(NIPBL/MAU2)
within
enhancers.
Here,
identify
two
clusters
LxxLL
motifs
NIPBL
sequence
regulate
dynamics,
interactome,
NIPBL-dependent
transcriptional
programs.
One
these
interacts
MAU2
necessary
for
maintenance
NIPBL–MAU2
heterodimer.
The
second
cluster
binds
specifically
ligand-binding
domains
steroid
receptors.
For
glucocorticoid
receptor
(GR),
examine
detail
its
interaction
surfaces
MAU2.
Using
AlphaFold2
molecular
docking
algorithms,
uncover
GR–NIPBL–MAU2
ternary
describe
importance
GR-dependent
gene
regulation.
Finally,
show
multiple
interact
NIPBL–MAU2,
likely
using
interfaces
other
than
those
characterized
GR.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 16, 2025
The
glucocorticoid
receptor
(GR)
is
an
essential
transcription
factor
that
controls
metabolism
and
homeostasis.
Glucocorticoids
(GCs)
activate
the
GR
upon
occupying
internal
ligand-binding
pocket
(LBP)
of
its
domain
(GR-LBD),
which
has
been
focus
most
previous
structure-function
studies.
Synthetic
GCs
such
as
dexamethasone
are
widely
used
to
treat
inflammatory
diseases,
but
their
chronic
use
results
in
major
side
effects,
whose
molecular
underpinnings
remain
unresolved.
Here
we
present
a
thorough
analysis
topography
GR-LBD
ability
bind
small-molecule
compounds,
especially
cholesterol
derivatives.
We
show
one
important
class
steroids,
bile
acids,
previously
unidentified
highly
conserved,
surface-exposed
cavities
on
GR-LBD.
acids
affect
turnover
self-assembly
living
cells,
modulating
transcriptional
activity.
These
findings
reveal
unrecognized
mechanism
regulation,
with
implications
for
design
novel
mechanisms
action.
Bile
modulate
activity
binding
exposed
allosteric
thereby
influencing
regulation
cells.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 12, 2024
Abstract
The
glucocorticoid
receptor
(GR)
is
a
leading
drug
target
due
to
its
anti-inflammatory
and
immunosuppressive
roles.
functional
oligomeric
conformation
of
full-length
GR
(FL-GR),
which
key
for
biological
activity,
remains
disputed.
Here
we
present
new
crystal
structure
agonist-bound
ligand-binding
domain
(GR-LBD)
comprising
eight
copies
non-canonical
dimer.
relevance
this
dimer
multimerization
in
living
cells
has
been
verified
by
studying
single-and
double-point
mutants
FL-GR
fluorescence
microscopy
(Number
&
Brightness)
transcriptomic
analysis.
Self-association
GR-LBD
basic
two
mutually
exclusive
assemblies
reveals
clues
activity
cells.
We
propose
model
the
multidomain
based
on
our
data
suggest
detailed
oligomerization
pathway.
This
reconciles
all
currently
available
structural
information
provides
more
comprehensive
understanding
rare
resistance
disorder
(Chrousos
syndrome).
