1M17,1XKK,2GS7,2GS6


Conserved Protein Domain Family
PTKc_EGFR

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cd05108: PTKc_EGFR (this model, PSSM-Id:173654 is obsolete and has been replaced by 270683)
Click on image for an interactive view with Cn3D
Catalytic domain of the Protein Tyrosine Kinase, Epidermal Growth Factor Receptor
Protein Tyrosine Kinase (PTK) family; Epidermal Growth Factor Receptor (EGFR); catalytic (c) domain. The PTKc family is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase (PI3K). PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER1, ErbB1) is a member of the EGFR (HER, ErbB) subfamily of proteins, which are receptor tyr kinases (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other tyr kinases, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Ligands for EGFR include EGF, heparin binding EGF-like growth factor (HBEGF), epiregulin, amphiregulin, TGFalpha, and betacellulin. Upon ligand binding, EGFR can form homo- or heterodimers with other EGFR subfamily members. The EGFR signaling pathway is one of the most important pathways regulating cell proliferation, differentiation, survival, and growth. Overexpression and mutation in the kinase domain of EGFR have been implicated in the development and progression of a variety of cancers. A number of monoclonal antibodies and small molecule inhibitors have been developed that target EGFR, including the antibodies Cetuximab and Panitumumab, which are used in combination with other therapies for the treatment of colorectal cancer and non-small cell lung carcinoma (NSCLC). The small molecule inhibitors Gefitinib (Iressa) and Erlotinib (Tarceva), already used for NSCLC, are undergoing clinical trials for other types of cancer including gastrointestinal, breast, head and neck, and bladder.
Statistics
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PSSM-Id: 173654
View PSSM: cd05108
Aligned: 8 rows
Threshold Bit Score: 653.215
Threshold Setting Gi: 18266816
Created: 8-Jun-2007
Updated: 17-Jan-2013
Structure
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Program:
Drawing:
Aligned Rows:
 
Conserved site includes 18 residues -Click on image for an interactive view with Cn3D
Feature 1:active site [active site]
Evidence:
  • Structure:2GS6_A; Human EGFR tyr kinase binds ATP analog and peptide substrate; defined at 3.5A contacts.
    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                       ##  ##                     #                                      
1M17_A         15 LRILKETEFKKIKVLGSGAFGTVYKGLWIPegekVKIPVAIKELREATspKANKEILDEAYVMASVDNPHVCRLLGICLt 94
1XKK_A         34 LRILKETEFKKIKVLGSGAFGTVYKGLWIPegekVKIPVAIKELREATspKANKEILDEAYVMASVDNPHVCRLLGICLt 113
2GS7_A         12 LRILKETEFKKIKVLGSGAFGTVYKGLWIPegekVKIPVAIKELREATspKANKEILDEAYVMASVDNPHVCRLLGICLt 91
2GS6_A         12 LRILKETEFKKIKVLGSGAFGTVYKGLWIPegekVKIPVAIKELREATspKANKEILDEAYVMASVDNPHVCRLLGICLt 91
gi 35903183   703 LRILKETEFKKIKVLGSGAFGTVHKGLWVPegenVKIPVAIKVLREATspKANKEIMDEAYVMASVEHPHVCRLLGICLt 782
gi 1070476    713 LRILKETEFKKVKVLGSGAFGTVYKGLWIPegekVKIPVAIKELREATspKANKEILDEAYVMASVDNPHVCRLLGICLt 792
gi 109631108  289 LRILKETEFKKIKVLGSGAFGTVYQGLWIPegegIKIPVAIKELREATspKANKEILDEAYVMASVENPYVCRLLGICLt 368
gi 18266816   702 LRILKETEFKKDRVLGSGAFGTVYKGLWNPdgenIRIPVAIKVLREATspKVNQEVLDEAYVMASVDHPHVCRLLGICLt 781
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                # #   #                                           ##            #        
1M17_A         95 sTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTpQHVKITDFGLAKLLG 174
1XKK_A        114 sTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTpQHVKITDFGLAKLLG 193
2GS7_A         92 sTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTpQHVKITDFGLAKLLG 171
2GS6_A         92 sTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTpQHVKITDFGLAKLLG 171
gi 35903183   783 sTVQLITQLMPYGCLLDYVRENKDRIGSQHLLNWCVQIAKGMNYLEERHLVHRDLAARNVLVKTpQHVKITDFGLAKLLN 862
gi 1070476    793 sTVQLITQLMPYGCLLDYIREHKDNIGSQYLLNWCVQIAKGMNYLEERRLVHRDLAARNVLVKTpQHVKITDFGLAKLLG 872
gi 109631108  369 sTVQLITQLMPFGCLLDYVRENKDNIGSRHLLNWCVQIAKGMNYLEERRLVHRDLAARNVLVKGpQHVKITDFGLAKLLG 448
gi 18266816   782 sAVQLVTQLMPYGCLLDYVRQHQERICGQWLLNWCVQIAKGMNYLEERHLVHRDLAARNVLLKNpNHVKITDFGLSKLLT 861
                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                     #####    #   #                                                      
1M17_A        175 AEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDV 254
1XKK_A        194 AEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDV 273
2GS7_A        172 AEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDV 251
2GS6_A        172 AEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDV 251
gi 35903183   863 ADEKEYHADGGKVPIKWMALESIQHRTYTHQSDVWSYGVTVWELMTFGTKPYDGIPASEIAGVLEKGERLPQPPICTIDV 942
gi 1070476    873 ADEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSVLEKGERLPQPPICTIDV 952
gi 109631108  449 ADEKAYHAEGGKVPIKWMALESILHRTYTHQSDVWSYGVTVWELMTFGLKPYDGIPASEISNILEKGERLPQPPICTIDV 528
gi 18266816   862 ADEKEYQADGGKVPIKWMALESILQWTYTHQSDVWSYGVTVWELMTFGSKPYDGIPAKEIASVLENGERLPQPPICTIEV 941
                         250       260       270       280       290       300       310
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
Feature 1                                                                                     
1M17_A        255 YMIMVKCWMIdADSRPKFRELIIEFSKMARDPQRYLVIQGdermhlpsptdsnfyralmdeeDMDDVVDADEYLIP 330
1XKK_A        274 YMIMVKCWMIdADSRPKFRELIIEFSKMARDPQRYLVIQGdermhlpsptdsnfyralmdeeDMDDVVDADEYLIP 349
2GS7_A        252 YMIMRKCWMIdADSRPKFRELIIEFSKMARDPQRYLVIQGdermhlpsptdsnfyralmdeeDMDDVVDADEYLIP 327
2GS6_A        252 YMIMVKCWMIdADSRPKFRELIIEFSKMARDPQRYLVIQGdermhlpsptdsnfyralmdeeDMDDVVDADEYLIP 327
gi 35903183   943 YMIMVKCWMIdAESRPRFRELIAEFTKMARDPSRYLVIQGddrmhlpspsd-skfyrslmsgELDEAVDADEYLVP 1017
gi 1070476    953 YMIMVKCWMIdADSRPKFRELIAEFSKMARDPPRYLVIQGdermhlpsptdskfyrtlmeeeDMEDIVDADEYLVP 1028
gi 109631108  529 YMIMVKCWMIdAESRPKFRELSAEFTKMARDPTRYLVIQGddrmhlpspve-skihpalveaGLGDIVDAEEYLLP 603
gi 18266816   942 YMIILKCWMIdPSSRPRFRELVGEFSQMARDPSRYLVIQGnlpslsdr------rlfsrllsSDDDVVDADEYLLP 1011

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