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Fig. 7 The solid-state NMR structure of Amt-bound M2 in lipid bilayers. (A) Side view showing
several key residues and Amt in the high-affinity luminal site. The time-averaged Amt orientation
is parallel to the channel axis. (B) Top view showing the Ser 31 and Val 27 pore radii. Adapted
from [
27
] with permission from Nature Publishing Group
neurotensin bound or unbound to the NTS1 receptor has also been investigated by
SSNMR, revealing a
-strand conformation upon binding [
94
]. The conformation
of the bradykinin (BK) peptide bound to the human bradykinin B2 receptor in
DDM, on the other hand, has recently been proposed to have a double S-shape
structure [
152
]. In the case of the human histamine H1 receptor, changes in the
protonation state of the ligand histamine binding to the receptor, SSNMR
experiments have revealed that the ligand can bind in a different cationic form
and a protonation switch might be part of the activation mechanism [
26
]. Another
outstanding example of these types of work is the study of influenza M2 proton
channel structure, function, and ligand binding conducted by the group of Hong [
27
,
28
]; through the extensive heteronuclear distance measurements and orientation
measurements, they have successfully proposed a structure model of the amanta-
dine binding to M2 in phospholipid bilayers, as shown in Fig.
7
. This study has
clearly demonstrated the ability of SSNMR to elucidate drug-membrane protein
interactions at atomic resolution and this is useful when conducting novel drug
design for human therapeutics.
b
3.4 Structural Changes upon Activation
Upon binding of agonists, which typically occurs in proximity to the extracellular
opening of the helical bundle, GPCRs undergo a series of structural changes that
cascade from the extracellular to the intracellular part of the receptor and ultimately
lead to G protein activation [
153
]. The multiple structural “switches” in rhodopsin
