4K5Y


Conserved Protein Domain Family
7tmB1_CRF-R1

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cd15445: 7tmB1_CRF-R1 
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corticotropin-releasing factor receptor 1, member of the class B family of seven-transmembrane G protein-coupled receptors
The vertebrate corticotropin-releasing factor (CRF) receptors are predominantly expressed in central nervous system with high levels in cortex tissue, brain stem, and pituitary. They have two isoforms as a result of alternative splicing of the same receptor gene: CRF-R1 and CRF-R2, which differ in tissue distribution and ligand binding affinities. Recently, a third CRF receptor (CRF-R3) has been identified in catfish pituitary. The catfish CRF-R1 is highly homologous to CRF-R3. CRF is a 41-amino acid neuropeptide that plays a central role in coordinating neuroendocrine, behavioral, and autonomic responses to stress by acting as the primary neuroregulator of the hypothalamic-pituitary-adrenal axis, which controls the levels of cortisol and other stress related hormones. In addition, the CRF family of neuropeptides also includes structurally related peptides such as mammalian urocortin, fish urotensin I, and frog sauvagine. The actions of CRF and CRF-related peptides are mediated through specific binding to CRF-R1 and CRF-R2. CRF and urocortin 1 bind and activate mammalian CRF-R1 with similar high affinities. By contrast, urocortin 2 and urocortin 3 do not bind to CRF-R1 or stimulate CRF-R1-mediated cAMP formation. Urocortin 1 also shows high affinity for mammalian CRF-R2, whereas CRF has significantly lower affinity for this receptor. These evidence suggest that urocortin 1 is an endogenous ligand for CRF-R1 and CRF-R2. The CRF receptors are members of the B1 subfamily of class B GPCRs, also referred to as secretin-like receptor family, which includes receptors for polypeptide hormones of 27-141 amino-acid residues such as secretin, glucagon, glucagon-like peptide (GLP), calcitonin gene-related peptide, and parathyroid hormone (PTH). These receptors contain the large N-terminal extracellular domain (ECD), which plays a critical role in hormone recognition by binding to the C-terminal portion of the peptide. On the other hand, the N-terminal segment of the hormone induces receptor activation by interacting with the receptor transmembrane domains and connecting extracellular loops, triggering intracellular signaling pathways. All members of the B1 subfamily preferentially couple to G proteins of G(s) family, which positively stimulate adenylate cyclase, leading to increased intracellular cAMP formation and calcium influx. However, depending on its cellular location and function, CRF receptors can activate multiple G proteins, which can in turn stimulate different second messenger pathways.
Statistics
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PSSM-Id: 320561
View PSSM: cd15445
Aligned: 5 rows
Threshold Bit Score: 445.533
Threshold Setting Gi: 524934145
Created: 31-Jan-2014
Updated: 26-Jul-2017
Structure
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Program:
Drawing:
Aligned Rows:
  next features
Conserved site includes 12 residues -Click on image for an interactive view with Cn3D
Feature 1:antagonist binding site [chemical binding site]
Evidence:
  • Structure:4K5Y: Human corticotropin-releasing factor receptor 1 (CRF-R1) binds antagonist CP-376395, 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                                                      #                                 
4K5Y_A        14 YHVAAIINYLGHCISLVALLVAFVLFLRARSIRCLRNIIHANLIAAFILRNATWFVVQLTMspevHQSNVGWCRLVTAAY 93
gi 2495062   121 YHIAVIINYLGHCVSLGTLLVAFVLFMRLRSIRCLRNIIHWNLITAFILRNATWFVVQLTMnpevHESNVVWCRLVTAAY 200
gi 544101    116 YHVAVIINYLGHCISLVALLVAFVLFLRLRSIRCLRNIIHWNLISAFILRNATWFVVQLTVspevHQSNVAWCRLVTAAY 195
gi 56566368  130 YHIAVIINYLGHCISLGALLVAFILFMRLRSIRCLRNIIHWNLITAFILRNATWFVVQLTMnpevHESNVIWCRLVTAAY 209
gi 147905576 116 YHIAIVINFLGHSISLCALLVAFILFLRLRSIRCLRNIIHWNLITAFILRNVTWFVMQLTLsheaHDSNVVWCRLVTIAH 195
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1               #  ##  #                                                                 
4K5Y_A        94 NYFHVTNFFWMFGEGCYLHTAIVLtnifemlrideglrlkiykdtegyytigighlltkspslsvakseldkaigrnsng 173
gi 2495062   201 NYFHVTNFFWMFGEGCYLHTAIVLty------------------------------------------------------ 226
gi 544101    196 NYFHVTNFFWMFGEGCYLHTAIVLty------------------------------------------------------ 221
gi 56566368  210 NYFHVTNFFWMFGEGCYLHTAIVLty------------------------------------------------------ 235
gi 147905576 196 NYFYVTNFFWMFGEGCYLHTAIVLty------------------------------------------------------ 221
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
4K5Y_A       174 vitkdeaeklfnqdvdaavrgilrnaklkpvydsldavrrsalinmvfqmgetgvagftnslrmlqqkrwdeaavnlaks 253
gi 2495062       --------------------------------------------------------------------------------
gi 544101        --------------------------------------------------------------------------------
gi 56566368      --------------------------------------------------------------------------------
gi 147905576     --------------------------------------------------------------------------------
                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
4K5Y_A       254 rwynqtpnrakrviatfrtgtwdayDRLRAWMFICIGWGVPFPIIVAWAIGKLYYDnEKCWAGKrpGVYTDYIYQGPMAL 333
gi 2495062   227 -----------------------stDKLRKWMFICIGWCIPFPIIVAWAIGKLYYDnEKCWFGKraGVYTDYIYQGPMIL 283
gi 544101    222 -----------------------stDRLRKWMFVCIGWGVPFPIIVAWAIGKLHYDnEKCWFGKrpGVYTDYIYQGPMIL 278
gi 56566368  236 -----------------------stDKLRKWMFICIGWCIPFPIIVAWAIGKLYYDnEKCWFGKraGIYTDYIYQGPMIL 292
gi 147905576 222 -----------------------stDKLRKWMFICIGWCIPFPIIVAWAIGKLYYDnEKCWFGKkaGVYTDFIYQGPVIL 278
                        330       340       350       360       370       380       390       400
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1         #  ##                               #   #  #   #                               
4K5Y_A       334 VLLINFIFLFNIVRILMTKLRASTtsETIQARKAVKATLVLLPLLGITYMLAFVNPGEDEvsRVVFIYFNAFLESFQGFF 413
gi 2495062   284 VLLINFIFLFNIVRILMTKLRASTtsETIQYRKAVKATLVLLSLLGITYMLFFVNPGEDEisRIVFIYFNSFLESFQGFF 363
gi 544101    279 VLLINFIFLFNIVRILMTKLRASTtsETIQYRKAVKATLVLLPLLGITYMLFFVNPGEDEvsRVVFIYFNSFLESFQGFF 358
gi 56566368  293 VLLINFIFLFNIVRILMTKLRASTtsETIQYRKAVKATLVLLPLLGITYMLFFVNPGEDEisQIVFIYFNSFLESFQGFF 372
gi 147905576 279 VLLINFIFLFNIVRILMTKLRASTtsETIQYRKAVKATLVLLPLLGITYMLFFVTPGEDEisRIVFIYFNSFLQSFQGFF 358
                        410       420
                 ....*....|....*....|..
Feature 1                              
4K5Y_A       414 VSVFACFLNsEVRSAAAAHHHH 435
gi 2495062   364 VSVFYCFLNsEVRSAVRKRWHR 385
gi 544101    359 VSVFYCFLNsEVRSAIRKRWRR 380
gi 56566368  373 VSVFYCFLNsEVRSAVRKRWHR 394
gi 147905576 359 VSVFYCFLNsEVRSAVRKRWHR 380

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