Sandbox Reserved 1649: Difference between revisions

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'''Transmembrane domain'''

The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization~~. Structurally, there is a small loop of 150 amino acids between M3 and M4~~. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>

The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>

M2 loop is a channel-lining loop and located in transmembrane domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref>

Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>

Structurally, there is a small loop of 150 amino acids between M3 and M4. Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>

'''CTD'''

Line 67:

NR1 and NR2A are assembled in a dimer, arranged in a back-to-back fashion, thanks to interactions between three different domains on each subunit: sites I, II and III.

- Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/2'>E68 in LBD</scene>) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/2'>F62 in LBD</scene>) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257.

- Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/1'> I52 in LBD</scene>), V526 (<scene name='86/868182/V64/1'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts

- Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/2'>I52 in LBD</scene>), V526 (<scene name='86/868182/V64/1'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts

Depending on the kind of NR2 (A-D) linked to NR1, the affinity of NR1 for glycine can be affected. Moreover, for a particular combination of NR1 and NR2 subunits, a negative cooperativity has been observed between glycine and glutamate binding. This leads to consider a possible allosteric coupling between NR1 and NR2. Thus, the importance of the structure of NR2A to make contacts with NR1 is obvious. But mechanistic explanation about the role that subunit-subunit contacts might have in NMDA receptor activity has not been found yet.

Sandbox Reserved 1649: Difference between revisions

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@@ Line 23: / Line 23: @@
 '''Transmembrane domain'''
-The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. Structurally, there is a small loop of 150 amino acids between M3 and M4. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>
+The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>
 M2 loop is a channel-lining loop and located in transmembrane domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref>
-Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>
+Structurally, there is a small loop of 150 amino acids between M3 and M4. Ethanol acts as an inhibitor on NMDAr. Phenylalanine at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>
 '''CTD'''
@@ Line 67: / Line 67: @@
 NR1 and NR2A are assembled in a dimer, arranged in a back-to-back fashion, thanks to interactions between three different domains on each subunit: sites I, II and III.
 -	Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/2'>E68 in LBD</scene>) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/2'>F62 in LBD</scene>) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257.
--	Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/1'> I52 in LBD</scene>), V526 (<scene name='86/868182/V64/1'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts
+-	Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/2'>I52 in LBD</scene>), V526 (<scene name='86/868182/V64/1'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts
 Depending on the kind of NR2 (A-D) linked to NR1, the affinity of NR1 for glycine can be affected. Moreover, for a particular combination of NR1 and NR2 subunits, a negative cooperativity has been observed between glycine and glutamate binding. This leads to consider a possible allosteric coupling between NR1 and NR2. Thus, the importance of the structure of NR2A to make contacts with NR1 is obvious. But mechanistic explanation about the role that subunit-subunit contacts might have in NMDA receptor activity has not been found yet.