Sandbox42: Difference between revisions

Line 41:

== '''Drug Binding Site''' ==

The NMDA Receptor primarily functions as a specific type of glutamate receptor. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begi. (8).

The NMDA Receptor primarily functions as a specific type of <scene name='Sandbox42/Glutamateglycine/1'>glutamate receptor</scene>. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begi. (8).

Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites (8)(9). Instead, they bind to the ion-channel in order to block the flow of ions, much in the same way that magnesium blocks transport. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. These are labelled relative to the N/Q/R site (position 0) as their proper orientation within the protein as a whole is still undetermined. The biding reaction of PCP and Ketamine to the NMDA receptor is thought to be stabilized via binding of the antagonist's amino group to these Asn oxygens, while Phe and Leu multi-carbon side-chains form bonds with the hydrophobic edges of the molecules. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section (10).

Sandbox42: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 41: / Line 41: @@
 == '''Drug Binding Site''' ==
-The NMDA Receptor primarily functions as a specific type of glutamate receptor. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begi. (8).
+The NMDA Receptor primarily functions as a specific type of <scene name='Sandbox42/Glutamateglycine/1'>glutamate receptor</scene>. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begi. (8).
 Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites (8)(9). Instead, they bind to the ion-channel in order to block the flow of ions, much in the same way that magnesium blocks transport. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. These are labelled relative to the N/Q/R site (position 0) as their proper orientation within the protein as a whole is still undetermined. The biding reaction of PCP and Ketamine to the NMDA receptor is thought to be stabilized via binding of the antagonist's amino group to these Asn oxygens, while Phe and Leu multi-carbon side-chains form bonds with the hydrophobic edges of the molecules. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section (10).