Biomedical Engineering Reference
In-Depth Information
7.3
INSULIN STRUCTURE
Human insulin, 5808 Da, consists of 51 amino acid residues in two
chains, with one intrachain disulfide and two interchain disulfides
(Figure 7.4). The insulin structure is folded as three a-helixes and a
b-strand, as has been documented by X-ray crystallography [33], as
well as NMR [34,35] and other techniques (Figure 7.5).
S
S
GI
VC
E
Q
C
T
S
I
C
S
L
Y
Q
L
E
N
Y
C
N
OH
H
S
S
S
S
F
V
N
Q
H
L
CS
G
H
L
V
E
A
L
Y
L
V
C
G
E
R
G
FY
F
T
P
K
T
H
OH
Figure 7.4 Human insulin sequence and disulfide pairings
B1
B1
c(phenol)
> mM
R
T
Figure 7.5 Insulin T- and R-folds. The monomer structures were extracted from crystal
structures 4IN and 2CTI. (see colour Plate 5)
There have been some suggestions that insulin undergoes a conforma-
tional change upon binding to its receptor [36]. Despite intense efforts, it
has not yet been possible to crystallize and elucidate the structure of
insulin in complex with its receptor [37-40]. Mutation studies like
Ala-scan and so on have given some information about the binding
epitopes of insulin [41,42]. The critical parts of the insulin structure
with regard to receptor affinity, and the parts that can be modified
without compromising the biological activity, are therefore quite well
recognized. It has been suggested that insulin contacts its receptor via two
separate epitopes [43,44]. Upon the extracellular binding of insulin to
the insulin receptor, the intracellular domain of the insulin receptor is
phosphorylated and a signal transduction occurs inside the cell, leading to
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