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Structure and Function

NR2A (GluN2A) is composed of Amino-terminal domain (ATD), segments S1 and S2 which formed ligand binding domain of glutamate, three transmembrane helices (M1, M3,and M4), cytoplasmic re-entrant pore loop (M2), and an intracellular C-terminal domain (CTD).

The ATD is constitued by first 383 aminoacids of NR2A. ATD is an alpha and beta protein class. Structure is bilobed and form clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. ^[2] Zn2+ may insert between 2 lobes and induces closure of channel by changing conformation of ATD. Zn increase affinity of glutamate on the LBD which reminds the desensization of AMPA and Kainate receptor. ^[3]

ATD allow to modulate NMDA receptor. Difference between différents NR2 is mainly regulated by ATD because diversity of ATD can modulate traffic in endoplasmic reticulum ans then affect the localisation of NMDAr. ATD of NR2A increase glutamate affinity, control channel’s opening with high probability and open duration, control glutamate deactivationtime course.^{[4] [5]}

LBD is constitued of two domains S1 (localised juste upstraem M1 transmembranaire domain) and S2 and has affinity for L-glutamate or sometime glycine. Positive charge of Amino-group of the agonist bind to negativ charges residue of the pocket D731. In GlurR, negative charge amino acid is a E731 and is able to form salt bridge with agonist. In NR2A D731 is not able to do salt bridge with amino group because aspartate is one methylene lacking to do it.

Amino group of agonist is stabilised by water mediated hydrogen bonds to amino acid E413 and Y761. 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. ^[6]

M2 loop is a channel-lining loop and located in transmembranaire domain. Two asparagines are located on N site of the domain and block Mg2+ and are permeable of Ca2+ ^[7]

CTD domain is the less conserved of NR2 domain and like ATD allows différents localisation of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable to receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD.^[7]

Disease

Relevance

Structural highlights

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