Molecular
and
Mechanistic
Underpinnings
of
Signal
Transduction
in
Membranes
-
NMR
Inspired
Studies
of
the
Conformational
Landscape
in
Enzymes
&
GPCRs
R.
Scott
Prosser
Departments
of
Chemistry
&
Biochemistry,
University
of
Toronto,
Canada
Friday,
October
11,
2019
1:00
p.m.
C2-361
(Reading
Room)
Abstract:
In
the
last
decade,
X-ray
crystallography
and
cryo-electron
microscopy
have
brought
about
a
renaissance
in
structural
biology.
Recent
atomic-resolution
structures
of
both
soluble
and
membrane
associated
proteins
provide
the
possibility
of
mechanistic
explanations
of
function
and
have
renewed
efforts
in
drug
discovery.
However,
the
“structure-function”
perspective
ignores
the
reality
of
protein
dynamics
and
the
fact
that
most
proteins
adopt
a
fluid
ensemble
of
functional
conformers
(states).
We
are
interested
in
the
role
of
this
ensemble
along
the
reaction
coordinate
pathway.
This
talk
will
review
studies
associated
with
a
homodimeric
enzyme,
fluroacetate
dehalogenase,
and
the
role
of
the
ensemble
in
accomplishing
catalysis.
We
will
then
present
recent
NMR
data
aimed
at
elucidating
the
key
functional
states
associated
with
the
adensoine
A
2A
G-Protein-Coupled
Receptor.
The
free-energy
landscape
is
tremendously
informative
with
regard
to
mechanistic
explanations
of
activation
and
signal
transduction
and
provides
new
opportunities
for
drug
discovery.