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NMDA receptor structures reveal subunit arrangement and pore architecture
Chia-Hsueh Lee1, Wei Lü1, Jennifer Carlisle Michel2
11] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2].
Nature
|July 11, 2014
Summary
Researchers revealed the molecular structure of the N-methyl-D-aspartate (NMDA) receptor, a key brain protein. This breakthrough offers new insights into NMDA receptor function and potential drug development targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- N-methyl-D-aspartate (NMDA) receptors are crucial for brain development and function, acting as coincidence detectors.
- Understanding the molecular structure of intact NMDA receptors is vital but has been challenging.
- These receptors require glycine, glutamate, and relief of magnesium block to open their ion channel.
Purpose of the Study:
- To determine the molecular structure of the Xenopus laevis GluN1-GluN2B NMDA receptor.
- To visualize the receptor in complex with an inhibitor, agonists, and an ion channel blocker.
Main Methods:
- X-ray crystallography was employed to obtain high-resolution structures.
- The study utilized the Xenopus laevis GluN1-GluN2B NMDA receptor.
Main Results:
- The NMDA receptor subunits are arranged in a 1-2-1-2 configuration with significant inter-domain interactions.
- The transmembrane domains reveal a closed ion channel, a vestibule for blocker/magnesium binding, and symmetric pore loops.
- Structures were determined in the presence of Ro25-6981 (allosteric inhibitor), partial agonists, and MK-801 (ion channel blocker).
Conclusions:
- The presented structures provide unprecedented insights into NMDA receptor architecture.
- These findings illuminate allosteric coupling mechanisms within the receptor.
- The structures offer a deeper understanding of NMDA receptor ion channel function and blocker interactions.
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