 |
PDBsum entry 4igt
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Membrane protein
|
PDB id
|
|
|
|
4igt
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Chemoenzymatic synthesis of new 2,4-Syn-Functionalized (s)-Glutamate analogues and structure-Activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters.
|
|
|
Authors
|
|
Z.Assaf,
A.P.Larsen,
R.Venskutonytė,
L.Han,
B.Abrahamsen,
B.Nielsen,
M.Gajhede,
J.S.Kastrup,
A.A.Jensen,
D.S.Pickering,
K.Frydenvang,
T.Gefflaut,
L.Bunch.
|
|
|
Ref.
|
|
J Med Chem, 2013,
56,
1614-1628.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
In the mammalian central nervous system, (S)-glutamate (Glu) is released from
the presynaptic neuron where it activates a plethora of pre- and postsynaptic
Glu receptors. The fast acting ionotropic Glu receptors (iGluRs) are ligand
gated ion channels and are believed to be involved in a vast number of
neurological functions such as memory and learning, synaptic plasticity, and
motor function. The synthesis of 14 enantiopure 2,4-syn-Glu analogues 2b-p is
accessed by a short and efficient chemoenzymatic approach starting from readily
available cyclohexanone 3. Pharmacological characterization at the iGluRs and
EAAT1-3 subtypes revealed analogue 2i as a selective GluK1 ligand with low
nanomolar affinity. Two X-ray crystal structures of the key analogue 2i in the
ligand-binding domain (LBD) of GluA2 and GluK3 were determined. Partial domain
closure was seen in the GluA2-LBD complex with 2i comparable to that induced by
kainate. In contrast, full domain closure was observed in the GluK3-LBD complex
with 2i, similar to that of GluK3-LBD with glutamate bound.
|
|
|
|
|
|
|
