Sandbox Reserved 1649: Difference between revisions
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<Structure load='2a5s' size='350' frame='true' align='right' caption='Crystal Structure Of The NR2A Ligand Binding Core In Complex With Glutamate' scene='Insert optional scene name here' /> | <Structure load='2a5s' size='350' frame='true' align='right' caption='Crystal Structure Of The NR2A Ligand Binding Core In Complex With Glutamate' scene='Insert optional scene name here' /> | ||
== NR2A (2A5S) == | == NR2A (2A5S) == | ||
NR2A is a protein which is a part of [https://en.wikipedia.org/wiki/NMDA_receptor NMDA receptors], heterodimer channels composed of four subunits. Indeed, NMDA receptors are made of the association between two NR2 and two NR1 proteins. NMDA receptors play a key role in mammalian central nervous system, as they act in Ca2+ influx in synapses in response to | NR2A is a protein which is a part of [https://en.wikipedia.org/wiki/NMDA_receptor NMDA receptors], heterodimer channels composed of four subunits. Indeed, NMDA receptors are made of the association between two NR2 and two NR1 proteins. NMDA receptors play a key role in mammalian central nervous system, as they act in Ca2+ influx in synapses in response to glutamate and glycine binding. Their role is essential for learning and memory. Variety of NR2 allows modulation of NMDAr. In the other hand, [https://www.youtube.com/watch?fbclid=IwAR163EHEh3RM8BXt-_4aiecrCgkF83HoyOefyU63d_CQwoqN5RHShYfLDnM&v=4-DuvwoH2zQ&feat NMDA receptor is related to AMPA receptor in the same synapse.] | ||
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== NR1/NR2A complex == | == NR1/NR2A complex == | ||
NR2A can be found in some NMDA receptors, in which NR2A is associated to NR1. NMDA receptors are necessarily heteromers of 4 subunits, organized as a dimer of dimers. These dimers are heterodimers constituted with glycine binding NR1 and glutamate binding subunits NR2. | NR2A can be found in some NMDA receptors, in which NR2A is associated to NR1. NMDA receptors are necessarily heteromers of 4 subunits, organized as a dimer of dimers. These dimers are heterodimers constituted with a glycine binding NR1 and a glutamate binding subunits NR2. | ||
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. | NR1 and NR2A are assembled in a dimer ([[https://proteopedia.org/wiki/index.php/2a5t?fbclid=IwAR0lozEgKTJwNjr16Sklgz0epz2LLAsw769SkhGuuuNIV3ZaEz2dY2EPNxk Complex NR1/NR2a]]), 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. | - 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/I52/2'>I52 in LBD</scene>), V526 (<scene name='86/868182/V64/2'>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/V64/2'>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. | 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. <ref name="ATD function">DOI 10.1038/nature04089</ref> | ||
Since the opening of the NMDA channel requires both glutamate and glycine, respectively detected by NR2 and NR1, the association between NR1 and NR2A is primordial. | Since the opening of the NMDA channel requires both glutamate and glycine, respectively detected by NR2 and NR1, the association between NR1 and NR2A is primordial. | ||
== Mutations == | == Mutations == | ||
