4OR2


Conserved Protein Domain Family
7tmC_mGluRs

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cd15045: 7tmC_mGluRs 
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metabotropic glutamate receptors, member of the class C family of seven-transmembrane G protein-coupled receptors
The metabotropic glutamate receptors (mGluRs) 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 I 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 (Gi/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: 320173
View PSSM: cd15045
Aligned: 23 rows
Threshold Bit Score: 317.265
Threshold Setting Gi: 358333709
Created: 10-Dec-2013
Updated: 26-Jul-2017
Structure
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Program:
Drawing:
Aligned Rows:
  next features
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 30913124  575 AWAIGPVTIACLGFMCTCIVITVFIKHNNtplVKASGRELCYILLFGVSLSYCMTFFFIakpsPVICALRRLGLGTSFAI 654
gi 405962956 293 PYVILIFVLSSVGIVLCSIVSVVFVFKRStpiVKATGFETSLVLLVGILLSYISPFILVsepsTASCAFFRIFLGLSYTM 372
gi 443734574 594 PWAISVLAMASVGILLTIVVLCIFVTYLDtpvIKASGRELSLVLMAGILLSYGTVFAVVappsVPICSISHLLLGLSYTV 673
gi 321457122 512 PWAAGSMAFALFGILLTLAVAFIFWRHRQtpvIKASGRELSAILLLATLCSFAMTFLIAsrptGFKCGVTRFSLGLTHTV 591
gi 646706872 530 PWAIAAMAVASLGILVTVFVFIIFWTYSDtpvVKASGRELSYLLLVGILASFCVTFVIVahptSFTCGLTRFFLGFCYTL 609
gi 291222301 555 SWGIGVLCFATAGVIVTSLVIVVFIKNNDtpiVKASGRELTYVLLVGIFLSYVISFVVVakpsVATCAATKFGIGFCFTL 634
gi 391329773 595 PWAIGSISFASIGMLVVIYISLVFRRFSDtpiIKASGRELSYLLLFGIFLSFSLTFVIVakptAVTCGLTRFFLGFCYTT 674
gi 645037416 572 PWAVSAMAVATCGILLTIFVLCVFWLYSEtpiIKASGRELSCLLLLGTLASFLMTFAIIarpnTQTCAITRFGIGLCYTL 651
gi 383849679 594 PWAVVATVNVFPGIAFTSFVCSVFWKYRDtpmIKASGRELSFLLLLGTFGCFSMTFAVVakpsVHSCAVVRFGIGFCYTI 673
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
4OR2_A       200 CYSALVTKTNRIarilagskkkic-------trkprfmsawaQVIIASILISVQLTLVVTLIIMEPpmpilsyp----si 268
gi 30913124  655 CYSALLTKTNCIarifdgvknga---------qrpkfispssQVFICLGLILVQIVMVSVWLILETpgtrrytlp--ekr 723
gi 405962956 373 AYSSILSKLMVYnrafdlqssiknktiqgqpllhrnictmktALVMTLTLSALHLFAIVFWIIGDTpvtvvsysitresa 452
gi 443734574 674 IYASILTKTSRIarifadhrgtp---------nktrftspgsQIVIVGVLVFGECVILAIWMAASPpkvihtypt---rg 741
gi 321457122 592 AFAAIAVKTNRVarifgtkktgsts----ltcprakyisprsQLAITGALTLIEVFVNASWLIYQPprtthifpd---ry 664
gi 646706872 610 CYAAIVTKTNRIarifsnrpisp---------hktrytspksQLVITALLTSVEVVINVSWLMYEPpsvthsfpt---re 677
gi 291222301 635 CYAAMLTKTNRIarifdrakssv---------kntkyisptsQLVICTCIMCVEFVVLGAWFAFQPprttyhhpv---re 702
gi 391329773 675 CYAAIVTKTSRIarifahgtkgr--------shkirytsprsQLLITALLVSVEVIVNVLWLMYDPpdatniypt---re 743
gi 645037416 652 CYSALVTKTNRIhrifnnatnsp---------hkprytsprsQLIITGIITFIEVLINGAWLLKAPpsatyafpt---rd 719
gi 383849679 674 CYAALATKINRIhrifndparsp---------rkrrytsprsQLAIASILSMIEVAFDASWLLKEPpavthsyps---rd 741
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                #    #  ##  #                                 #  ##  #   #         ##  #
4OR2_A       269 kevyliCNTSNLGVVAPLGYNGLLIMSCTYYAFKTRNVpanFNEAKYIAFTMYTTCIIWLAFVPIYFg----SNYKIITT 344
gi 30913124  724 etvilkCNVKDSSMLISLTYDVVLVILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTM 803
gi 405962956 453 ignrscIDLRNFSYFVSLGWSFLLMIACLVFALKTRKLpdgMNDSHEIMYCSFTSFILWITFIPLYAfs-dnKVVKVMSL 531
gi 443734574 742 qnvlacDNAEGAHSLIPLIYPFLLLLLCAVYVFKTRKTpdgFNETRLIAFTSYTTVVIWLAFTPLYAiv-tdSHVRGFIL 820
gi 321457122 665 krvlicEGMDHYTYLVGLVYPLILIGCCTVYAFQTRKCpggFNEARYIGFTTYTTCVLWMAFIPLFLta-ptTTLRIVTL 743
gi 646706872 678 srmlicEGLDGYSYMVGLLYPFVLIGLCTAYAVKTRKCpggFNETRHIAFTNYTAIIIWLAFVPLYLas-nsNSIRVVTL 756
gi 291222301 703 kneltcSGATDATYLIGLMYPFFLMVFCTVYAFKTRNCpegFNEAKYIGFSMYTTCVIWLSFVPIYFvssrnVALRVTTL 782
gi 391329773 744 esvlicARSDDHKYLIGLVYPFILMCFCTVYAFKTRKCpdgFNEARYLTFTNYTTCVVWLAFLPLFVls-tnNAIRAVTL 822
gi 645037416 720 trlricQGFDDRSYTIGLIYPFILIVVCTVYAVKTRKCpegFNETRYIAFTNYTTMILWLAFVPLYLas-tsNAIRVVTL 798
gi 383849679 742 anvrvcKGSEDGSYVIGLLYPFVLTVASTVYAIKTRKCpegFNETRRIAFANYATIILWLAFVPLYLas-ssNEVKVITL 820
                        250       260
                 ....*....|....*....|....*
Feature 1          #   #                  
4OR2_A       345 CFAVSLSVTVALGCMFTPKMYIIIA 369
gi 30913124  804 CISVSLSGFVVLGCLFAPKVHIVLF 828
gi 405962956 532 SIALVVHGTLCLLCLFVTKIYIVVF 556
gi 443734574 821 AVALCLTAFLCLACLFIPKVYICLL 845
gi 321457122 744 AMSMSISGIVQLACLFAPKVYIVLC 768
gi 646706872 757 AISLSLSGLVQLACLFFPKLYIVLF 781
gi 291222301 783 SVSVGLCATVILCCIFAPKLYIILI 807
gi 391329773 823 SFLLNLSGTVQIFCLFVPKVYIALF 847
gi 645037416 799 ALSLSLSALVQLACLFFPKVYIVLM 823
gi 383849679 821 ALSLSLNGLVQLLCLFLPKVYVVLI 845

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