4OR2,4OO9


Conserved Protein Domain Family
7tmC_mGluR_group1

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cd15285: 7tmC_mGluR_group1 
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metabotropic glutamate receptors in group 1, member of the class C family of seven-transmembrane G protein-coupled receptors
Group 1 mGluRs includes mGluR1 and mGluR5, as well as their closely related invertebrate receptors. They are homodimeric class C G-protein coupled receptors which are activated by glutamate, the major excitatory neurotransmitter of the CNS. mGluRs are involved in regulating neuronal excitability and synaptic transmission via intracellular activation of second messenger signaling pathways. While the ionotropic glutamate receptor subtypes (AMPA, NMDA, and kainite) mediate fast excitatory postsynaptic transmission, mGluRs are known to mediate slower excitatory postsynaptic responses and to be involved in synaptic plasticity in the mammalian brain. In addition to seven-transmembrane helices, the class C GPCRs are characterized by a large N-terminal extracellular Venus flytrap-like domain, which is composed of two adjacent lobes separated by a cleft which binds an endogenous ligand. Moreover, they exist as either homo- or heterodimers, which are essential for their function. For instance, mGluRs form homodimers via interactions between the N-terminal Venus flytrap domains and the intermolecular disulphide bonds between cysteine residues located in the cysteine-rich domain (CRD). At least eight different subtypes of metabotropic receptors (mGluR1-8) have been identified and further classified into three groups based on their sequence homology, pharmacological properties, and signaling pathways. Group 1 (mGluR1 and mGluR5) receptors are predominantly located postsynaptically on neurons and are involved in long-term synaptic plasticity in the brain, including long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. They are coupled to G(q/11) proteins, thereby activating phospholipase C to generate inositol-1,4,5-triphosphate (IP3) and diacyglycerol (DAG), which in turn lead to Ca2+ release and protein kinase C activation, respectively. Group 1 mGluR expression is shown to be strongly upregulated in animal models of epilepsy, brain injury, inflammatory, and neuropathic pain, as well as in patients with amyotrophic lateral sclerosis or multiple sclerosis. Group 2 (mGluR2 and mGluR3) and 3 (mGluR4, mGluR6, mGluR7, and mGluR8) receptors are predominantly localized presynaptically in the active region of neurotransmitter release. They are coupled to G(i/o) proteins, which leads to inhibition of adenylate cyclase activity and cAMP formation, and consequently to a decrease in protein kinase A (PKA) activity. Ultimately, activation of these receptors leads to inhibition of neurotransmitter release such as glutamate and GABA via inhibition of Ca2+ channels and activation of K+ channels. Furthermore, while activation of Group 1 mGluRs increases NMDA (N-methyl-D-aspartate) receptor activity and risk of neurotoxicity, Group 2 and 3 mGluRs decrease NMDA receptor activity and prevent neurotoxicity.
Statistics
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PSSM-Id: 320412
View PSSM: cd15285
Aligned: 22 rows
Threshold Bit Score: 304.175
Threshold Setting Gi: 156384916
Created: 7-Feb-2014
Updated: 26-Jul-2017
Structure
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Program:
Drawing:
Aligned Rows:
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Conserved site includes 21 residues -Click on image for an interactive view with Cn3D
Feature 1:allosteric modulator binding site [chemical binding site]
Evidence:
  • Structure:4OR2: Human mGluR1 receptor binds a negative allosteric modulator FITM, contacts at 4A
    View structure with Cn3D

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                  #           ##  ##  #  
4OR2_A        120 IESIIAIAFSCLGILVTLFVTLIFVLYRDTpvVKSSSRELCYIILAGIFLGYVCPFTLIakptTTSCYLQRLLVGLSSAM 199
gi 215494831  113 TASIIVMVVCSFVMLSTGAVATIYIRYITTplIKASSRELSFVVLLGILCATASTFAVLakptPIVCAIERFMPAFGVAT 192
gi 156356306  588 PWKAVVATAAGVGVVVTMFVIGVFIKFKDTplIMAAGREVSTLLFTGMIMCYALAFVMVvppnTTLCGIRRFGTGISFCL 667
gi 156367294  542 SWSIMVTCFATVGIICVLGVSVIFIMFSETplVKASGRELTATLLIGLFLCYVEGIMLIlrpsVFVCGLQRFGVGFAPCV 621
gi 193202792  576 FGHILALVLAVTGIITSMATLAVFLRHNSTpvVKSTTRELSYIILSGLVACYAVSFALLatpsTTSCFITRVIPPIAFAV 655
gi 321455131  606 AQSIVAVTLSVVGLLATVATAAVFAWHNNTpvVKASTRELTYIILVGMALCYLTTFPLLavpsRLSCTLSRILPGFSFSL 685
gi 555933773  610 PTCLTGITFACVGGILTFLILIIFIIHRDTavVKVSTRELMWIILLAMLLAHASVSTILlrpsVTTCALQRSLPALAFTA 689
gi 541046016  504 SGIVLALVLASAGIITTLLTTLVFVQHNHTpvVKSTTRELSYIILSGIMACYAVSFAILarpsFATCFLTRTVPPIAFSI 583
gi 478251679  537 RSAVVAMVFSILGLLTTAFAFIVLIQHNNTpvVKSSSKELCYLILAGMTVAHASIFAMLskpsPSSCASTRLLPGVAFAM 616
gi 645014800  596 VEAIIAMTLAAIGLLATFITCHIFIRHNNTpvVKASTRELSYLILAGMTLSHFSVLPILakptYTSCTLSRLMPGISFAM 675
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                       # 
4OR2_A        200 CYSALVTKTNRIARILagskkkictrkprfmsawAQVIIASILISVQLTLVVTLIIMEPpmpilsy-psikevyLICNTS 278
gi 215494831  193 IHAAIFTKTNRIARILavkeskmfsrkrrfmsttSQLVITGLLILGQAIVSGTMLAIEPpgaqdff-aapnqvsLICNTS 271
gi 156356306  668 LYTSLLVKTNRIARIFsgtksp------sfispkSQLFITLLIISPVLTITLLEFYFHPpkikyth--lekynlLSCSNK 739
gi 156367294  622 CYAALLIKTNRIARIFakserstk--ppdfinpaSQLLILAAVVGVEVVLAGVGLGYWSpkqtekf-ptksdilSTCNIQ 698
gi 193202792  656 VYSALLTKTNRIARILagskkriltkkprflttfSQVVITWILVAVQCVIVGVGLMRDWpdatyakyalprkliLECDTE 735
gi 321455131  686 IFAALLTKTNRIARILagskkrictrksrwlsltAQILITMAMIGVEVMLIVSMLILEPadavkff-psrsrvlIICDTT 764
gi 555933773  690 IYGALVTKTNRIARILegskrillk-krrflstsAQLVITGSLLAVESLAVIVMLILEPpkdtvryskdkirarISCNTS 768
gi 541046016  584 IYSALLTKTNRIARILagskkriltkkprflstsSQVVITWILVGIECVIVAVGVMEEMpqagfdpyyqpsrmvLVCSTT 663
gi 478251679  617 IYSALLTKTNRIARILagskrnfpnrkllfmsatAQVMIALSLISLEALANGAMLYLQPpaiafvy--lpnktlMECDIS 694
gi 645014800  676 IYASLFTKTNRIARILagskkrfpkrkplfmsatAQIMITCILITIEVAVAATMLMMEPampirvh-pardrtvLTCATT 754
                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1            #  ##  #                                 #  ##  #   #               ##  #  # 
4OR2_A        279 NLGVVAPLGYNGLLIMSCTYYAFKTRNVpanFNEAKYIAFTMYTTCIIWLAFVPIYFg----------SNYKIITTCFAV 348
gi 215494831  272 ELANFLGLSYDFLLILLCTVWAVKTRNVpenFNEAKMIGFAMYATVVIWIAYLAVYCg---------sERNRELSLCLAM 342
gi 156356306  740 EIAVITKLCYNVLLILLCTYYAFRTRKTplnFNEAKFIGFCMYTTCVIWIAFLPLYFga--------gGGFEGLAVCFSA 811
gi 156367294  699 DYDLVVAMSYNVLLILLCTIYAFRTRKTpanFNEARYIGFAMYTTCVIWLAFLPVQIgv-------ndKDYKTLTLSINV 771
gi 193202792  736 TKSFLIPFFWDFFLITLCTLYAFKTRNLpenFNEAKFIGFTMYCTVVVWIAFLVLHMg----------TTHKALVMSFSY 805
gi 321455131  765 TRGLIAPLGFDFFLIGMCTVYAVKTRNLpenFNEAKFIGFAMYTTCVIWVAFVPIYFs---------gNESKTITLCMCV 835
gi 555933773  769 KRGTVIPLTFPIFLIGMCTIYAIKTRNLpqnFNEAKFIGFTMYTTCVLWLAIIPVYLs----------GYEAEMVLTLCI 838
gi 541046016  664 TFAFLSPFLWNLFLISLCTLYAIKTRNLpenFNEAKFIGFTMYCTLVVWTAFIVLHLg----------TTNKALTMSFSF 733
gi 478251679  695 FEAIVVPLAFDFVLILLCTVYAIKSRNVpenFSEAKFIGFAMYTTCVIWIAFVPIYFg----------SGAKTITMCMCV 764
gi 645014800  755 PRAVLSPLAFDALLIGLCTLYAIKTRNVpenFNEAKFIGFAMYTTCVIWIAFVPIYFgsetkrlfkdaKLSQVITMCMCV 834
                         250       260
                  ....*....|....*....|.
Feature 1           #                  
4OR2_A        349 SLSVTVALGCMFTPKMYIIIA 369
gi 215494831  343 NVSSFMVLMFLFIPKIYIVLF 363
gi 156356306  812 VFSATTILVFIFAPKVYIVIF 832
gi 156367294  772 TLNATTLLLCVFGPKVYIVLF 792
gi 193202792  806 SLSASVALALLFFPKLYIILM 826
gi 321455131  836 SLSAVVTLVLLFGPKLYIIIF 856
gi 555933773  839 SVSASIALVILFFPKTYIILC 859
gi 541046016  734 SLSASVALVLLFFPKLYIILF 754
gi 478251679  765 TLSALVTWVFLFVPKLYIILL 785
gi 645014800  835 TLSASVTLVFLFMPKLYIIVL 855

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