Biomedical Engineering Reference
In-Depth Information
Phe320
Ser321
Leu322
GLy323
The dopamine
transporter (DAT)
Asp79
Ala77
Phe76
Y V
D
S
F
S
N
L
A S
F
F A
G
G
V
Ser422
Ala423
Gly426
Phe326
Val328
Asn157
Tyr156
Gly153
Val152
Ser149
N
C
(a)
DAT-dopamine
DAT-CFT
TM8
TM8
TM3
TM1
TM1
TM3
L80
L80
D79
4
D79
Y156
1
3
S422
Y156
S422
1
5
N157
2
N157
V152
6
TM6
F76
TM6
F76
V328
V152
F326
V328
F326
S149
S149
(b)
(c)
FIGURE 14.5 Models of DAT/ligand complexes. (a) Two-dimensional schematic representation of the human
dopamine transporter (hDAT). The colored circles denote residues that interact with either dopamine or the
cocaine analogue CFT in the molecular models. Red circles, side chain interaction; orange, only backbone inter-
action. (b) Docked dopamine and (c) CFT in DAT. TMs 1, 3, 6, and 8 are shown in various shades of blue; the
other TMs and intra- and extracellular loops have been removed for clarity. The ligands are shown in green.
Sodium and chloride ions are shown as purple and salmon spheres, respectively. The protonated amine of dop-
amine forms a salt-bridge with the Asp79 side chain (motif 1 in b). A polar interaction is also predicted between
the amine of CFT and Asp79 (motif 1 in c). Dopamine further engages in hydrogen bonds with exposed backbone
carbonyls of the unwound regions of TM1 and TM6. The binding of dopamine results in an additional aromatic-
aromatic interaction between the catechol ring and Tyr156 (motif 2). Tyr156 also forms a hydrogen bond with
Asp79 (motif 3) and a hydrophobic interaction with Leu80 (motif 4). In the CFT model, Tyr156 interacts in an
edge-to-face manner with the methylester subtituent on the tropane ring (motif 5) leading to reorientation of the
Tyr156 side chain and disruption of the hydrogen bond between Tyr156 and Asp79 seen in the dopamine model.
Finally, there is CFT-specii c hydrogen-bond interaction between the nitrogen of Asn157 and the l uoride atom of
CFT (motif 6). (Modii ed from Beuming, J. et al., Nat. Neurosci ., 11, 780, 2008. With permission.)
 
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