Biomedical Engineering Reference
In-Depth Information
a
1
29
H
SQGT
F
T
S
D
Y
S
K
Y
L
D
S
R
R
A
Q
D
F
V
Q
W
L
M
N
T
Glucagon
1
31
GPL-1
H
AEGT
F
T
S
D
V
S
S
Y
L
E
G
Q
A
A
K
E
F
I
A
W
L
V
K
G
R
G
1
33
GLP-2
H
ADGS
F
S
D
E
M
N
T
I
L
D
N
L
A
A
R
D
F
I
N
W
L
I
K
T
K
I
T
D
b
Name
His1
Asp9
Lys12
Cter
Des-His-glucagon
removed
[1-N α-trinitrophenylhis
dine,
12-homoarginine]-glucagon
α-trinitrophenyl
his
dine
homoarginine
Des-His
1
[Glu
9
]glucagon amide
removed
Glu
amidated
c
BI 32169
1
L
P
G
9
19
W
D
I
P
GW
NT
P
WA C
G
S
C
P
Fig. 3.3
Glucagon peptides and antagonists of their receptors.
a
Primary structures of glucagon,
GLP-1 and GLP-2. The amino acids conserved between glucagon, GLP-1 and GLP-2 are coloured
in
green
; those conserved between glucagon and GLP-1 only are shown in
blue
. The amino acids
in glucagon important for receptor binding and/or signal transduction are circled in
bold
.
b
Table
showing the positions modified from glucagon in selected peptidic antagonists of the glucagon
receptor (Cho et al.
2012
): des-His glucagon (Goldfine et al.
1972
), [1-N α-trinitrophenylhistidine,
12-homoarginine]-glucagon (Bregman et al.
1980
), des-His
1
[Glu
9
]glucagon amide (Unson et al.
1991
).
c
Primary structure of BI 32169 (see secondary structure in Fig.
3.2
)
regulation of carbohydrate, lipid and amino acid metabolisms and act on separate
receptors (Bataille
1996
; Drucker
2001
). Glucagon is synthesized and secreted
mainly by the β cells of the pancreas. It counteracts hypoglycaemia and opposes
insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby
increasing blood glucose concentration (Quesada et al.
2008
). In diabetes, the bal-
ance of glucose fluxes is disturbed, partly as a result of inappropriate glucagon
secretion (Unger and Orci
1975
; Gosmain et al.
2013
). As previously mentioned for
ETs, discrepancies between the structures of glucagon derived from X-ray crystal-
lography and NMR have been reported. While the crystal structure of glucagon ob-
tained in 1975 revealed a helical conformation (Sasaki et al.
1975
), NMR structural
analyses indicated that glucagon was unordered in aqueous solution (Braun et al.
1983
). It is now established that most class B ligands show little, if any, ordered
structure in aqueous solutions but can form α-helices in the presence of organic
solvents, or lipids, or upon crystallization (Parthier et al.
2009
).
The receptors of glucagon GLP-1 and GLP-2 are seven transmembrane-span-
ning proteins, all belonging to the class B of GPCRs (Harmar
2001
), and more
specifically to the glucagon receptor family (Mayo et al.
2003
). GPCRs from class
B are characterized by (1) a long extracellular N-terminal domain with three con-
served disulfide bridges and large extracellular loops that form multiple binding
pockets for peptide ligands and (2) a disulfide bond linking Cys residues from the
first and second extracellular loops (Harmar
2001
; Siu et al.
2013
). The N-terminal
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