Sandbox42: Difference between revisions

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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).

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. 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).

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).

As shown in figures 1-3, Ketamine, PCP, and MK-801 all share similar cyclic carbon structures which can easily bind and block such a narrow opening (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). Given that PCP is often smoked in recreational abuse, the heat causes a reaction that breaks the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. PC is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).

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 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).
-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. 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).
+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).
 As shown in figures 1-3, Ketamine, PCP, and MK-801 all share similar cyclic carbon structures which can easily bind and block such a narrow opening (10). Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a much higher binding affinity for the NMDA receptor than (r)-Ketamine, yet PCP has shown to have an even greater binding affinity than either. This can cause problems as PCP will bind so strongly that it eventually causes severe damage to the protein structure through its inhibitory nature (8)(11). Given that PCP is often smoked in recreational abuse, the heat causes a reaction that breaks the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. PC is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine. This binding reaction, and subsequent destruction of the NMDA receptor is thought to be the cause of many neurological disorders involving psychosis such as Schizophrenia. A natural degradation of NMDA receptors may be involved in Alzheimer's Disease (AD) given the receptor's importance in learning and memory (8)(11)(12).