Sandbox Reserved 1649: Difference between revisions

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'''Ligand binding domain (LBD)'''

LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist bind to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/1'>D213</scene>) is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/1'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/1'>E14</scene>).<scene name='86/868182/Y243_et_e14/1'>Click here if you want to see E14 and Y243 together.</scene> The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/1'>T114</scene> et <scene name='86/868182/S112/1'>S112</scene>.

LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist bind to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/1'>D213</scene>) is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/1'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/1'>E14</scene>).<scene name='86/868182/Y243_et_e14/1'>Click here if you want to see E14 and Y243 together. </scene> The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/1'>T114</scene> et <scene name='86/868182/S112/1'>S112</scene>.<scene name='86/868182/T114_et_s112/1'>(T114 and S112)

On the other hand, <scene name='86/868182/Aa_in_interaction_with_nr1/1'>amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part).

'''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.<ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>

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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 (E68 in LBD) makes a salt bridge with R755 of NR1, F524 (F62 in LBD) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257.

- Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/1'>E68 in LBD) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/1'>F62 in LBD</scene></scene></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 (I52 in LBD), V526 (V64 in LBD), 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/I52/1'>I52 in LBD</scene>I52), 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 15: / Line 15: @@
 '''Ligand binding domain (LBD)'''
-LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist bind to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/1'>D213</scene>) is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/1'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/1'>E14</scene>).<scene name='86/868182/Y243_et_e14/1'>Click here if you want to see E14 and Y243 together.</scene> The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/1'>T114</scene> et <scene name='86/868182/S112/1'>S112</scene>.
+LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for glutamate or sometime glycine. Positive charge of amino-group of the agonist bind to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/1'>D213</scene>) is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/1'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/1'>E14</scene>).<scene name='86/868182/Y243_et_e14/1'>Click here if you want to see E14 and Y243 together. </scene> The high affinity for glutamate agonist may be because of van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/1'>T114</scene> et <scene name='86/868182/S112/1'>S112</scene>.<scene name='86/868182/T114_et_s112/1'>(T114 and S112)
+On the other hand, <scene name='86/868182/Aa_in_interaction_with_nr1/1'>amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part).
 '''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.<ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>
@@ Line 32: / Line 33: @@
 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 (E68 in LBD) makes a salt bridge with R755 of NR1, F524 (F62 in LBD) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257.
+-	Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/1'>E68 in LBD) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/1'>F62 in LBD</scene></scene></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 (I52 in LBD), V526 (V64 in LBD), 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/I52/1'>I52 in LBD</scene>I52), 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.