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Figure 5.
Figure 5: Agonist-induced conformational changes in the dimer
and gating model. a, Overlap of the S1S2J -L483Y dimers bound
with either an agonist (AMPA, green) or an antagonist (DNQX,
red). The relative movement of the linker region, which connects
the ligand-binding core to the channel-forming segments, is
represented by the difference in position of Ile 633 in the two
structures. Distances between Ile 633 on two protomers are 28.3
Å in the DNQX structure and 36.3 Å in the AMPA structure. In
addition, Ile 633 rotates around the 2-fold axis by 1.25° and
moves 2.5 Å along the 2-fold axis, away from the membrane. b, A
model for glutamate receptor activation and desensitization.
Domain 1 and domain 2 of the ligand-binding core are labelled D1
and D2, respectively. Transmembrane segments of each subunit are
indicated by a single green cylinder and the N-terminal domain
(ATD) has not been included in the model. Each subunit binds a
single agonist (A, red circle) and exists in three distinct
conformations: closed (C), open (O) and desensitized (D). The
closed and open states share the same S1S2 dimer interface.
After the binding of agonist, closure of domain 2 towards domain
1 opens the channel gate, whereas closure of domain 1 towards
domain 2 disrupts the dimer interface and desensitizes the
receptor. The states are connected by using a simplified model
for activation and desensitization, more complex versions of
which quantitatively describe AMPA receptor responses10,25. A
hypothetical plot of the free-energy change occurring during
activation and desensitization is shown in the lower left panel
for the wild-type (black line), L483Y (green line) and S754D
(red line) species.
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