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1.A.10.1.20
Heteromeric ionotropic NMDA receptor (NMDAR) consisting of two subunits, GluN1 (938 aas) and GluN2A (1464 aas).  Positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site have been proposed, and differences in the structural and dynamic behavior of the channel proteins in the presence of Mg2+ or Ca2+ have been analyzed (Mesbahi-Vasey et al. 2017). GRIN variants in receptor M2 channel pore-forming loop are associated with neurological diseases (Li et al. 2019). Disease-associated variants have revealed mechanistic aspect of the NMDA receptor (Amin et al. 2021). Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors (Iacobucci et al. 2021). The gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors have been reported (Wang et al. 2021). GluN2A and GluN2B NMDA receptors apparently use distinct allosteric routes (Tian et al. 2021). A negative allosteric modulatory site in the GluN1 M4 determines the efficiency of neurosteroid modulation (Langer et al. 2021). Excitatory signaling mediated by NMDAR is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs can be used for treating depression, Alzheimer's disease, and epilepsy. Chou et al. 2022 monitored the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site. The channel blockers form interactions with pore-lining residues, which control mostly off-speeds but not on-speeds (Chou et al. 2022).  NMDAR channel blockers include MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration (Wilcox et al. 2022). Pregnane-based steroids are  positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations (Kysilov et al. 2022). The NMDA receptor C-terminal domain signals in development, maturity, and disease (Haddow et al. 2022). Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors (Furon et al. 2023). Two gates mediate NMDA receptor activity and are under subunit-specific regulation (Amin et al. 2023). One of the main molecular mechanisms of ketamine action is the blockage of NMDA-activated glutamate receptors (Pochwat 2022). The S1-M1 linker of the NMDA receptor controls channel opening (Xie et al. 2023). Binding and dynamics demonstrated the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit (Chen et al. 2023). The functional effects of disease-associated NMDA receptor variants have been reviewed (Moody et al. 2023). Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema (Zheng et al. 2023).  Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decreases NMDAR surface expression and reduces potentiating effects of neurosteroids (Kysilov et al. 2024).  De novo GRIN variants in the M3 helix associated with neurological disorders control channel gating of the NMDA receptor (Xu et al. 2024).

Accession Number:Q12879
Protein Name:Glutamate receptor ionotropic, NMDA 2A
Length:1464
Molecular Weight:165283.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate

Cross database links:

Structure:
3NFL   5H8F   5H8H   5H8N   5H8Q   5I2K   5I2N   5KCJ   5KDT   5TP9   [...more]

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MGRVGYWTLL VLPALLVWRG PAPSAAAEKG PPALNIAVML GHSHDVTERE LRTLWGPEQA 
61:	AGLPLDVNVV ALLMNRTDPK SLITHVCDLM SGARIHGLVF GDDTDQEAVA QMLDFISSHT 
121:	FVPILGIHGG ASMIMADKDP TSTFFQFGAS IQQQATVMLK IMQDYDWHVF SLVTTIFPGY 
181:	REFISFVKTT VDNSFVGWDM QNVITLDTSF EDAKTQVQLK KIHSSVILLY CSKDEAVLIL 
241:	SEARSLGLTG YDFFWIVPSL VSGNTELIPK EFPSGLISVS YDDWDYSLEA RVRDGIGILT 
301:	TAASSMLEKF SYIPEAKASC YGQMERPEVP MHTLHPFMVN VTWDGKDLSF TEEGYQVHPR 
361:	LVVIVLNKDR EWEKVGKWEN HTLSLRHAVW PRYKSFSDCE PDDNHLSIVT LEEAPFVIVE 
421:	DIDPLTETCV RNTVPCRKFV KINNSTNEGM NVKKCCKGFC IDILKKLSRT VKFTYDLYLV 
481:	TNGKHGKKVN NVWNGMIGEV VYQRAVMAVG SLTINEERSE VVDFSVPFVE TGISVMVSRS 
541:	NGTVSPSAFL EPFSASVWVM MFVMLLIVSA IAVFVFEYFS PVGYNRNLAK GKAPHGPSFT 
601:	IGKAIWLLWG LVFNNSVPVQ NPKGTTSKIM VSVWAFFAVI FLASYTANLA AFMIQEEFVD 
661:	QVTGLSDKKF QRPHDYSPPF RFGTVPNGST ERNIRNNYPY MHQYMTKFNQ KGVEDALVSL 
721:	KTGKLDAFIY DAAVLNYKAG RDEGCKLVTI GSGYIFATTG YGIALQKGSP WKRQIDLALL 
781:	QFVGDGEMEE LETLWLTGIC HNEKNEVMSS QLDIDNMAGV FYMLAAAMAL SLITFIWEHL 
841:	FYWKLRFCFT GVCSDRPGLL FSISRGIYSC IHGVHIEEKK KSPDFNLTGS QSNMLKLLRS 
901:	AKNISSMSNM NSSRMDSPKR AADFIQRGSL IMDMVSDKGN LMYSDNRSFQ GKESIFGDNM 
961:	NELQTFVANR QKDNLNNYVF QGQHPLTLNE SNPNTVEVAV STESKANSRP RQLWKKSVDS 
1021:	IRQDSLSQNP VSQRDEATAE NRTHSLKSPR YLPEEMAHSD ISETSNRATC HREPDNSKNH 
1081:	KTKDNFKRSV ASKYPKDCSE VERTYLKTKS SSPRDKIYTI DGEKEPGFHL DPPQFVENVT 
1141:	LPENVDFPDP YQDPSENFRK GDSTLPMNRN PLHNEEGLSN NDQYKLYSKH FTLKDKGSPH 
1201:	SETSERYRQN STHCRSCLSN MPTYSGHFTM RSPFKCDACL RMGNLYDIDE DQMLQETGNP 
1261:	ATGEQVYQQD WAQNNALQLQ KNKLRISRQH SYDNIVDKPR ELDLSRPSRS ISLKDRERLL 
1321:	EGNFYGSLFS VPSSKLSGKK SSLFPQGLED SKRSKSLLPD HTSDNPFLHS HRDDQRLVIG 
1381:	RCPSDPYKHS LPSQAVNDSY LRSSLRSTAS YCSRDSRGHN DVYISEHVMP YAANKNNMYS 
1441:	TPRVLNSCSN RRVYKKMPSI ESDV