Journal article
The Structure of (−)-Kaitocephalin Bound to the Ligand Binding Domain of the (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor, GluA2
The Journal of biological chemistry, Vol.287(49), pp.41007-41013
11/30/2012
Handle:
https://hdl.handle.net/2376/113959
PMCID: PMC3510803
PMID: 23076153
Abstract
Background:
The natural product (−)-kaitocephalin is a potential scaffold for development of subtype-specific glutamate receptor antagonists.
Results:
The crystal structure of (−)-kaitocephalin bound to an AMPA receptor ligand binding domain was determined.
Conclusion:
The orientation of (−)-kaitocephalin in the binding site can explain the subtype selectivity of the parent compound.
Significance:
Comparisons with the structure of other glutamate receptors provides avenues for development of new subtype-specific antagonists.
Glutamate receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and excessive stimulation of these receptors is involved in a variety of neurological disorders and neuronal damage from stroke. The development of new subtype-specific antagonists would be of considerable therapeutic interest. Natural products can provide important new lead compounds for drug discovery. The only natural product known to inhibit glutamate receptors competitively is (−)-kaitocephalin, which was isolated from the fungus
Eupenicillium shearii
and found to protect CNS neurons from excitotoxicity. Previous work has shown that it is a potent antagonist of some subtypes of glutamate receptors (AMPA and NMDA, but not kainate). The structure of kaitocephalin bound to the ligand binding domain of the AMPA receptor subtype, GluA2, is reported here. The structure suggests how kaitocephalin can be used as a scaffold to develop more selective and high affinity antagonists for glutamate receptors.
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Details
- Title
- The Structure of (−)-Kaitocephalin Bound to the Ligand Binding Domain of the (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor, GluA2
- Creators
- Ahmed H Ahmed - From theMakoto Hamada - theTetsuro Shinada - theYasufumi Ohfune - theLaksiri Weerasinghe - thePhilip P Garner - theRobert E Oswald - From the
- Publication Details
- The Journal of biological chemistry, Vol.287(49), pp.41007-41013
- Academic Unit
- Chemistry, Department of
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- R01-GM068935 / National Institutes of Health
- Identifiers
- 99900547687301842
- Language
- English
- Resource Type
- Journal article