Quarterly Reviews of Biophysics,
Год журнала:
2021,
Номер
54
Опубликована: Янв. 1, 2021
Over
the
past
decade,
structural
biology
of
membrane
proteins
(MPs)
has
taken
a
new
turn
thanks
to
epoch-making
technical
progress
in
single-particle
electron
cryo-microscopy
(cryo-EM)
as
well
improvements
sample
preparation.
The
present
analysis
provides
an
overview
extent
and
modes
usage
various
types
surfactants
for
cryo-EM
studies.
Digitonin,
dodecylmaltoside,
protein-based
nanodiscs,
lauryl
maltoside-neopentyl
glycol,
glyco-diosgenin,
amphipols
(APols)
are
most
popular
at
vitrification
step.
Surfactant
exchange
is
frequently
used
between
MP
purification
grid
preparation,
requiring
extensive
optimization
each
time
study
undertaken.
variety
both
experimental
approaches
over
few
years
bears
witness
need
continue
developing
innovative
optimizing
conditions
possibilities
offered
by
novel
APols
EM
applications
discussed.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(11)
Опубликована: Март 9, 2023
Adenosine
triphosphate-binding
cassette
(ABC)
transporters,
such
as
multidrug
resistance
protein
1
(MRP1),
protect
against
cellular
toxicity
by
exporting
xenobiotic
compounds
across
the
plasma
membrane.
However,
constitutive
MRP1
function
hinders
drug
delivery
blood–brain
barrier,
and
overexpression
in
certain
cancers
leads
to
acquired
chemotherapy
failure.
Small-molecule
inhibitors
have
potential
block
substrate
transport,
but
few
show
specificity
for
MRP1.
Here
we
identify
a
macrocyclic
peptide,
named
CPI1,
which
inhibits
with
nanomolar
potency
shows
minimal
inhibition
of
related
transporter
P-glycoprotein.
A
cryoelectron
microscopy
(cryo-EM)
structure
at
3.27
Å
resolution
that
CPI1
binds
same
location
physiological
leukotriene
C4
(LTC
4
).
Residues
interact
both
ligands
contain
large,
flexible
sidechains
can
form
variety
interactions,
revealing
how
recognizes
multiple
structurally
unrelated
molecules.
binding
prevents
conformational
changes
necessary
adenosine
triphosphate
(ATP)
hydrolysis
suggesting
it
may
therapeutic
candidate.
Communications Biology,
Год журнала:
2023,
Номер
6(1)
Опубликована: Фев. 3, 2023
Abstract
Multidrug
resistance-associated
proteins
are
ABC
C-family
exporters.
They
crucial
in
pharmacology
as
they
transport
various
substrates
across
membranes.
However,
the
role
of
degenerate
nucleotide-binding
site
(NBS)
remains
unclear
likewise
interplay
with
surrounding
lipid
environment.
Here,
we
propose
a
dynamic
and
structural
overview
MRP1
from
ca
.
110
μs
molecular
dynamics
simulations.
ATP
binding
to
NBS1
is
likely
maintained
along
several
cycles.
Asymmetric
NBD
behaviour
ensured
by
lower
signal
transduction
NBD1
rest
protein
owing
absence
ball-and-socket
conformation
between
coupling
helices.
Even
though
lipids
play
an
active
allosteric
communication
substrate-binding
pocket
NBDs,
our
results
suggest
that
composition
has
limited
impact,
mostly
affecting
kinetics.
We
believe
work
can
be
extended
other
NBS
provide
hints
for
deciphering
mechanistic
differences
among
transporters.
Structure,
Год журнала:
2023,
Номер
31(11), С. 1407 - 1418.e6
Опубликована: Сен. 7, 2023
Multidrug
resistance-associated
protein
4
(MRP4)
is
an
ATP-binding
cassette
(ABC)
transporter
expressed
at
multiple
tissue
barriers
where
it
actively
extrudes
a
wide
variety
of
drug
compounds.
Overexpression
MRP4
provides
resistance
to
clinically
used
antineoplastic
agents,
making
highly
attractive
therapeutic
target
for
countering
multidrug
resistance.
Here,
we
report
cryo-EM
structures
physiologically
relevant
states
lipid
bilayer-embedded
human
MRP4,
including
complexes
between
and
two
widely
chemotherapeutic
agents
complex
its
native
substrate.
The
display
clear
similarities
distinct
differences
in
the
coordination
these
chemically
diverse
substrates
and,
combination
with
functional
mutational
analysis,
reveal
molecular
details
transport
mechanism.
Our
study
key
insights
into
unusually
broad
substrate
specificity
constitutes
important
contribution
toward
general
understanding
transporters.
Proceedings of the National Academy of Sciences,
Год журнала:
2021,
Номер
118(21)
Опубликована: Май 21, 2021
Significance
The
Ycf1p
structure
provides
an
atomic
model
for
the
TMD0
domain
of
ABCC
transporters
and
two
segments
regulatory
(R)
region
that
links
NBD1
to
TMD2.
orientation
in
differs
from
seen
SUR1,
protein
K
ATP
channels,
demonstrating
flexibility
TMD0/ABC
core
contacts.
suggests
how
posttranslational
modifications
R
modulate
ABC
activity
a
mechanistic
understanding
several
diseases
occur
due
mutation
human
homologs
Ycf1p.
Quarterly Reviews of Biophysics,
Год журнала:
2021,
Номер
54
Опубликована: Янв. 1, 2021
Over
the
past
decade,
structural
biology
of
membrane
proteins
(MPs)
has
taken
a
new
turn
thanks
to
epoch-making
technical
progress
in
single-particle
electron
cryo-microscopy
(cryo-EM)
as
well
improvements
sample
preparation.
The
present
analysis
provides
an
overview
extent
and
modes
usage
various
types
surfactants
for
cryo-EM
studies.
Digitonin,
dodecylmaltoside,
protein-based
nanodiscs,
lauryl
maltoside-neopentyl
glycol,
glyco-diosgenin,
amphipols
(APols)
are
most
popular
at
vitrification
step.
Surfactant
exchange
is
frequently
used
between
MP
purification
grid
preparation,
requiring
extensive
optimization
each
time
study
undertaken.
variety
both
experimental
approaches
over
few
years
bears
witness
need
continue
developing
innovative
optimizing
conditions
possibilities
offered
by
novel
APols
EM
applications
discussed.