Biochemistry,
Journal Year:
2024,
Volume and Issue:
63(11), P. 1474 - 1492
Published: May 14, 2024
Allostery
is
a
fundamental
mechanism
driving
biomolecular
processes
that
holds
significant
therapeutic
concern.
Our
study
rigorously
investigates
how
two
distinct
machine-learning
algorithms
uniquely
classify
already
close-to-active
DFG-in
states
of
TAK1,
differing
just
by
the
presence
or
absence
its
allosteric
activator
TAB1,
from
an
ensemble
mixture
conformations
(obtained
2.4
μs
molecular
dynamics
(MD)
simulations).
The
novelty,
however,
lies
in
understanding
deeper
algorithmic
potentials
to
systematically
derive
diverse
set
differential
residue
connectivity
features
reconstruct
essential
mechanistic
architecture
for
TAK1-TAB1
allostery
such
biochemical
scenario.
While
recursive,
random
forest-based
workflow
displays
potential
conducting
discretized,
hierarchical
derivation
features,
multilayer
perceptron-based
approach
gains
considerable
efficacy
revealing
fluid
connected
patterns
when
hybridized
with
mutual
information
scoring.
Interestingly,
both
pipelines
benchmark
similar
directions
functional
conformational
changes
TAK1's
activation.
findings
significantly
advance
depth
highlighting
crucial
activation
signatures
along
directed
C-lobe
→
loop
ATP
pocket
channel
flow,
including
(1)
αF-αE
biterminal
alignments
and
(2)
"catalytic"
drift
toward
kinase
active
site.
Besides,
some
novel
hotspots
(K253,
Y206,
N189,
etc.)
are
further
recognized
as
TAB1
sensors,
transducers,
responders,
E70
mutation
site,
precisely
mapping
important
structural
segments
sequential
execution.
Hence,
our
work
demonstrates
navigate
through
greater
depths
dimensions
dynamic
machineries
leveraging
standard
ML
methods
suitable
streamlined
workflows
adaptive
specific
system
objectives.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Aug. 9, 2024
Abstract
G
protein
coupled
receptors
(GPCRs)
are
the
largest
family
of
signalling
proteins
and
highly
successful
drug
targets.
To
date,
most
GPCR
drugs
interact
with
binding
pocket
for
natural
ligand,
typically
near
extracellular
part
transmembrane
region.
Recent
advancements
in
structural
biology
have
identified
additional
allosteric
sites
other
parts
these
receptors.
Allosteric
provide
several
theoretical
advantages,
including
ability
to
modulate
ligand
function,
there
is
a
need
better
ways
study
how
ligands
bind
diVerent
sites.
We
developed
an
approach
multiple
same
receptor
based
on
sequential
resonance
energy
transfer
between
two
fluorescent
bound
simultaneously
GPCR.
use
this
gain
insight
into
interactions
clinically
relevant
receptor.
This
method
will
important
information
aid
development
new
drugs.
