The Innovation,
Journal Year:
2025,
Volume and Issue:
6(3), P. 100774 - 100774
Published: Jan. 18, 2025
Traditional
medicines
serve
not
only
as
an
integral
part
of
medical
treatments
prescribed
by
healthcare
providers
but
also
a
fundamental
reservoir
for
novel
molecular
scaffolds.
However,
gaps
remain
in
our
understanding
the
mechanisms
underlying
their
activity.
A
superfamily
membrane
proteins,
G
protein-coupled
receptors
(GPCRs),
have
been
demonstrated
to
be
potential
targets
several
compounds
isolated
from
traditional
medicines.
Given
that
GPCRs
approximately
one-third
all
marketed
drugs,
they
may
compelling
repurposing
Despite
this
potential,
research
investigating
activity
or
ligands
across
GPCRome,
library
human
GPCRs,
is
scarce.
Drawing
on
functional
and
structural
knowledge
presently
available,
review
contemplates
prospective
trends
GPCR
drug
discovery,
proposes
innovative
strategies
medicines,
highlights
ligand
screening
approaches
identifying
drug-like
molecules.
To
discover
bioactive
molecules
either
directly
bind
indirectly
modify
function,
genome-wide
pan-GPCR
discovery
platform
was
designed
identification
components
targets,
evaluation
pharmacological
profiles.
This
aims
aid
exploration
all-sided
relations
between
GPCRome
using
advanced
high-throughput
techniques.
We
present
various
used
many,
including
ourselves,
illuminate
previously
unexplored
aspects
GPCRs.
Current Opinion in Structural Biology,
Journal Year:
2024,
Volume and Issue:
86, P. 102792 - 102792
Published: March 1, 2024
Allostery
is
a
fundamental
mechanism
of
cellular
homeostasis
by
intra-protein
communication
between
distinct
functional
sites.
It
an
internal
process
proteins
to
steer
interactions
not
only
with
each
other
but
also
biomolecules
such
as
ligands,
lipids,
and
nucleic
acids.
In
addition,
allosteric
regulation
particularly
important
in
enzymatic
activities.
A
major
challenge
structural
molecular
biology
today
unraveling
sites
proteins,
elucidate
the
detailed
allostery
development
drugs.
Here
we
summarize
recently
developed
tools
approaches
which
enable
elucidation
regulatory
hotspots
correlated
motion
biomolecules,
focusing
primarily
on
solution-state
nuclear
magnetic
resonance
spectroscopy
(NMR).
These
open
avenue
towards
rational
understanding
provide
essential
information
for
design
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: May 13, 2024
Abstract
G-protein-coupled
receptors
(GPCRs)
play
pivotal
roles
in
various
physiological
processes.
These
are
activated
to
different
extents
by
diverse
orthosteric
ligands
and
allosteric
modulators.
However,
the
mechanisms
underlying
these
variations
signaling
activity
modulators
remain
largely
elusive.
Here,
we
determine
three-dimensional
structure
of
μ-opioid
receptor
(MOR),
a
class
A
GPCR,
complex
with
G
i
protein
an
modulator,
BMS-986122,
using
cryogenic
electron
microscopy.
Our
results
reveal
that
BMS-986122
binding
induces
changes
map
densities
corresponding
R167
3.50
Y254
5.58
,
key
residues
structural
motifs
conserved
among
GPCRs.
Nuclear
magnetic
resonance
analyses
MOR
absence
enhances
formation
interaction
between
thus
stabilizing
fully-activated
conformation,
where
intracellular
half
TM6
is
outward-shifted
allow
for
protein.
findings
illuminate
like
can
potentiate
activation
through
alterations
conformational
dynamics
core
region
Together,
our
demonstrate
regulatory
GPCRs,
providing
insights
into
rational
development
therapeutics
targeting
Trends in Pharmacological Sciences,
Journal Year:
2023,
Volume and Issue:
44(12), P. 978 - 990
Published: Oct. 31, 2023
Serotonin
is
a
neurotransmitter
regulating
numerous
physiological
processes
also
modulated
by
drugs,
for
example,
schizophrenia,
depression,
migraine,
and
obesity.
However,
these
drugs
typically
have
adverse
effects
caused
promiscuous
binding
across
12
serotonin
more
than
20
homologous
receptors.
Recently,
structures
of
the
entire
receptor
family
uncovered
molecular
ligand
recognition.
Here,
we
present
map
19
'selectivity
hotspots',
that
is,
nonconserved
site
residues
governing
selectivity
via
favorable
target
interactions
or
repulsive
'off-target'
contacts.
Furthermore,
review
functional
rationale
from
observed
ligand-binding
affinities
mutagenesis
effects.
Unifying
knowledge
underlying
specific
probes
critical
toward
characterization
different
receptors
alleviation
Quarterly Reviews of Biophysics,
Journal Year:
2025,
Volume and Issue:
58
Published: Jan. 1, 2025
Abstract
Allostery
describes
the
ability
of
biological
macromolecules
to
transmit
signals
spatially
through
molecule
from
an
allosteric
site
–
a
that
is
distinct
orthosteric
binding
sites
primary,
endogenous
ligands
functional
or
active
site.
This
review
starts
with
historical
overview
and
description
classical
example
allostery
hemoglobin
other
well-known
examples
(aspartate
transcarbamoylase,
Lac
repressor,
kinases,
G-protein-coupled
receptors,
adenosine
triphosphate
synthase,
chaperonin).
We
then
discuss
fringe
allostery,
including
intrinsically
disordered
proteins
inter-enzyme
influence
dynamics,
entropy,
conformational
ensembles
landscapes
on
mechanisms,
capture
essence
field.
Thereafter,
we
give
over
central
methods
for
investigating
molecular
covering
experimental
techniques
as
well
simulations
artificial
intelligence
(AI)-based
methods.
conclude
allostery-based
drug
discovery,
its
challenges
opportunities:
recent
advent
AI-based
methods,
compounds
are
set
revolutionize
discovery
medical
treatments.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 8, 2025
Abstract
The
M
5
muscarinic
acetylcholine
receptor
(M
mAChR)
represents
a
promising
therapeutic
target
for
neurological
disorders.
However,
the
high
conservation
of
its
orthosteric
binding
site
has
posed
significant
challenges
drug
development.
While
selective
positive
allosteric
modulators
(PAMs)
offer
potential
solution,
structural
understanding
mAChR
and
sites
remained
limited.
Here,
we
present
2.8
Å
cryo-electron
microscopy
structure
complexed
with
heterotrimeric
G
q
protein
agonist
iperoxo,
completing
active-state
characterization
family.
To
identify
-selective
PAMs,
implemented
an
integrated
approach
combining
mutagenesis,
pharmacological
assays,
biology,
molecular
dynamics
simulations.
Our
mutagenesis
studies
revealed
that
PAMs
bind
outside
previously
characterized
sites.
Subsequently,
obtained
2.1
co-bound
PAM
VU6007678,
revealing
novel
pocket
at
extrahelical
interface
between
transmembrane
domains
3
4
was
confirmed
through
These
findings
demonstrate
diverse
mechanisms
regulation
in
mAChRs
highlight
value
integrating
approaches
to
Frontiers in Endocrinology,
Journal Year:
2023,
Volume and Issue:
14
Published: June 26, 2023
G
protein-coupled
receptors
(GPCRs)
represent
the
target
for
approximately
a
third
of
FDA-approved
small
molecule
drugs.
The
adenosine
A
1
receptor
(A
R),
one
four
GPCR
subtypes,
has
important
(patho)physiological
roles
in
humans.
R
well-established
regulation
cardiovascular
and
nervous
systems,
where
it
been
identified
as
potential
therapeutic
number
conditions,
including
cardiac
ischemia-reperfusion
injury,
cognition,
epilepsy,
neuropathic
pain.
drugs,
typically
orthosteric
ligands,
have
undergone
clinical
trials.
To
date,
none
progressed
into
clinic,
predominantly
due
to
dose-limiting
unwanted
effects.
development
allosteric
modulators
that
topographically
distinct
binding
site
promising
approach
overcome
current
limitations.
Pharmacological
parameters
affinity,
efficacy
cooperativity,
can
be
optimized
regulate
activity
with
high
subtype,
spatial
temporal
selectivity.
This
review
aims
offer
insights
highlight
recent
advances
structural
understanding
modulation.
