Conserved Protein Domain Family
beta_secretase_like

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cd05473: beta_secretase_like 
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Beta-secretase, aspartic-acid protease important in the pathogenesis of Alzheimer's disease.
Beta-secretase also called BACE (beta-site of APP cleaving enzyme) or memapsin-2. Beta-secretase is an aspartic-acid protease important in the pathogenesis of Alzheimer's disease, and in the formation of myelin sheaths in peripheral nerve cells. It cleaves amyloid precursor protein (APP) to reveal the N-terminus of the beta-amyloid peptides. The beta-amyloid peptides are the major components of the amyloid plaques formed in the brain of patients with Alzheimer's disease (AD). Since BACE mediates one of the cleavages responsible for generation of AD, it is regarded as a potential target for pharmacological intervention in AD. Beta-secretase is a member of pepsin family of aspartic proteases. Same as other aspartic proteases, beta-secretase is a bilobal enzyme, each lobe contributing a catalytic Asp residue, with an extended active site cleft localized between the two lobes of the molecule. The N- and C-terminal domains, although structurally related by a 2-fold axis, have only limited sequence homology except the vicinity of the active site. This suggests that the enzymes evolved by an ancient duplication event. The enzymes specifically cleave bonds in peptides which have at least six residues in length with hydrophobic residues in both the P1 and P1' positions. The active site is located at the groove formed by the two lobes, with an extended loop projecting over the cleft to form an 11-residue flap, which encloses substrates and inhibitors in the active site. Specificity is determined by nearest-neighbor hydrophobic residues surrounding the catalytic aspartates, and by three residues in the flap. The enzymes are mostly secreted from cells as inactive proenzymes that activate autocatalytically at acidic pH. This family of aspartate proteases is classified by MEROPS as the peptidase family A1 (pepsin A, clan AA).
Links
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BioAssay Targets and Results
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CID: 44394812
AID: 238396
GI: 296434407
IC50: 0.00032µM
more
Binding affinity against Beta-secretase
Target Name: Beta-secretase 1
Chemical Name: CHEMBL183214
IC50: 0.00032µM
CID: 44305509
AID: 42091
GI: 296434407
IC50: 0.00032µM
more
Binding affinity for human brain memapsin 2 beta-Secretase (BACE)
Target Name: Beta-secretase 1
Chemical Name: CHEMBL264379
IC50: 0.00032µM
CID: 44397266
AID: 239175
GI: 296434407
IC50: 0.0003µM
more
Binding affinity towards Beta-secretase determined using continuum electrostatics solvation
Target Name: Beta-secretase 1
Chemical Name: CHEMBL363255
IC50: 0.0003µM
Statistics
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PSSM-Id: 133140
View PSSM: cd05473
Aligned: 11 rows
Threshold Bit Score: 647.944
Threshold Setting Gi: 156379353
Created: 8-Sep-2006
Updated: 17-Jan-2013
Structure
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Program:
Drawing:
Aligned Rows:
Hierarchy
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Display:
 
Conserved site includes 2 residues -Click on image for an interactive view with Cn3D
Feature 1:catalytic residue [active site]
Evidence:
  • Structure:1ym4_a; catalytic aspartic acid residues of human Beta Secretase
    View structure with Cn3D
  • Comment:The two ASPs at the active site plays key catalytic roles in the pepsin family and conserved for all family members.

cd05473 is part of a hierarchy of related CD models.
Use the graphical representation to navigate this hierarchy.
cd05473 is a member of the superfamily cl11403.
cd00303:retropepsin_likecd05470:pepsin_retropepsin_likecd05471:pepsin_likecd05472:cnd41_likecd05473:beta_secretase_likecd05474:SAP_likecd05475:nucellin_likecd05476:pepsin_A_like_plantcd05477:gastricsincd05478:pepsin_Acd05479:RP_DDIcd05480:NRIP_Ccd05481:retropepsin_like_LTR_1cd05482:HIV_retropepsin_likecd05483:retropepsin_like_bacteriacd05484:retropepsin_like_LTR_2cd05485:Cathepsin_D_likecd05486:Cathespin_Ecd05487:renin_likecd05488:Proteinase_A_fungicd05489:xylanase_inhibitor_I_likecd05490:Cathepsin_D2cd06094:RP_Saci_likecd06095:RP_RTVL_H_likecd06096:Plasmepsin_5cd06097:Aspergillopepsin_likecd06098:phytepsin1156933111563793531YM4 A2HIZ A11241906341944860472085863341680466852602EWY A1180839211156933111563793531YM4 A2HIZ A11241906341944860472085863341680466852602EWY A118083921
cd05473 Sequence Cluster
cd05473 Sequence Cluster
Sub-family Hierarchy
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 cd05473 Branch
 Whole Hierarchy
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CD Hierarchy
Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                             #                                                          
1YM4_A        27 GQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHG 106
gi 112419063  73 GQGYYVEMRVGTPPQTLNILVDTGSSNFAVGAAPHPFLKRYYHRQHSRTYRDVRRGVYVPYTQGKWEGELGTDLVTIPHG 152
gi 41944860   77 GQGYYIEMAVGSPAQRLNILVDTGSSNFAVGAAAHPFLHRYYHRSLSSSYRDLGRGVYVPYTQGRWEGELGTDVVSVPCG 156
gi 6685260    89 GRGYYLEMLIGTPPQKLQILVDTGSSNFAVAGTPHSYIDTYFDTERSSTYRSKGFDVTVKYTQGSWTGFVGEDLVTIPKG 168
gi 33416804   73 GRGYYLELLIGSPPQKVNILVDTGSSNFAVAGSPNPDVNTFFDSKLSTSYQSLNTEVTVRYTQGSWTGLLGKDVVSIPKG 152
gi 47208586   24 GRGYYIEMSIGTPGQKMNILVDTGSSNFAVAAAPHPFITHFFNTALSTSYRSAGRPVAVRYTQGNWEGELGVDLVSMPTG 103
gi 118083921  71 GRGYFLEMLIGTPPQALNILVDTGSSNFAVAGVPDPDVTSYFNTELSSTYQSQGIEVTVKYSQGSWTGVLGTDVVTIPKG 150
2HIZ_A        74 GQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHG 153
2EWY_A        12 GRGYYLEMLIGTPPQKLQILVDTGSSNFAVAGTPHSYIDTYFDTERSSTYRSKGFDVTVKYTQGSWTGFVGEDLVTIPKG 91
gi 115693311  78 GLGYYIEVDIGTPPQKLNVLIDTGSSNFAVAASSHNAISTYYRRNESSTYEDQGTYVKVPYTQGEWSGDLGQDLVQIASL 157
gi 156379353   9 GQGYYIASNLGSPPQRINVLVDTGSSNFAVAASAHPYIPYYFHIDKSTSYKDLNKPVSVPYTQGSWEGELGSDLIKFVDG 88
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
1YM4_A       107 pnvTVRANIAAITESDKFFIngSNWEGILGLAYAEIARPDdslepFFDSLVKQth-vPNLFSLQLCGAGfplnqs----- 180
gi 112419063 153 pnvTVTANIAAITDSDKFFIngSNWEGILGLAYAEIARPDdtlepFFDSLVKQtr-vPNIFSLQLCGTGfhfnes----- 226
gi 41944860  157 pnvSLRANIAAITQSDRFFIngSNWEGILGLAYAEIARPDetlepFFDSLLRQst-vADVFSLQLCGAGynhnyst---- 231
gi 6685260   169 fntSFLVNIATIFESENFFLpgIKWNGILGLAYATLAKPSssletFFDSLVTQan-iPNVFSMQMCGAGlpvag------ 241
gi 33416804  153 vngTFLINIASIFQSESFFLpnINWQGILGLAYSTLAKPSssvepFFDSLVQQen-iPDVFSMQMCGAGqsspg------ 225
gi 47208586  104 pngTVPINIAAILSSDGFFLpdIHWQGILGLAYPLLARPDssvtpFFDSLVRQlg-iPDVFSLQMCGAGlsagaa----- 177
gi 118083921 151 idgRYTINIATILESENFFLpgVKWHGILGLAYDTLAKPSssvetFFDSLVKQak-iPNIFSLQMCGAGlpvsg------ 223
2HIZ_A       154 pnvTVRANIAAITESDKFFIngSNWEGILGLAYAEIARPDdslepFFDSLVKQth-vPNLFSLQLCGAGfplnqs----- 227
2EWY_A        92 fntSFLVNIATIFESENFFLpgIKWNGILGLAYATLAKPSssletFFDSLVTQan-iPNVFSMQMCGAGlpvag------ 164
gi 115693311 158 gnqSFQANIAAITESKMFFLndSRWQGILGLGYAEIARPDssvepFFDSLTSQts-iQDIFALQMCGALastndtnlgss 236
gi 156379353  89 pnvTLRVDVASILQSENFFIngSMWEGILGLGYARLAKPDssvtpVFDQFVLDhgveKDSFSMQLCGSSeidps------ 162
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                         #              
1YM4_A       181 --evlasvGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFE 258
gi 112419063 227 --dtsasvGGSMVIGGIDPSLYIGSIWYTPIRKEWYYEVIIVKIEINGQDLHMDCKEYNYDKSIVDSGTTNLRLPKRVFD 304
gi 41944860  232 --gssstvGGSMIIGGVDPSLYVGELWYTPIRREWYYEVIIVRIEVNGQDLNMDCKEYNYDKSIVDSGTTNLRLPRKVFQ 309
gi 6685260   242 ----sgtnGGSLVLGGIEPSLYKGDIWYTPIKEEWYYQIEILKLEIGGQSLNLDCREYNADKAIVDSGTTLLRLPQKVFD 317
gi 33416804  226 ----nginAGSLVLGGVEPSLYKGNIWYTPITEEWYYQVEVLKFEVGGQRLNLDCTVYNSDKAIVDSGTTLLRLPDKVFN 301
gi 47208586  178 ---aaaalGGSLIMGGTEPTLHRGPVWYTPIVEEWYYQVEVLKLEVGDQNLDLDCREYNTDKAIVDSGTTLLRLPVPVFN 254
gi 118083921 224 ----sgtnGGSLVLGGIEPSLYKGNIWYTPIKEEWYYQVEILKLEVGGQNLELDCREYNADKAIVDSGTTLLRLPQKVFS 299
2HIZ_A       228 --evlasvGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFE 305
2EWY_A       165 ----sgtnGGSLVLGGIEPSLYKGDIWYTPIKEEWYYQIEILKLEIGGQSLNLDCREYNADKAIVDSGTTLLRLPQKVFD 240
gi 115693311 237 adgpveevIGSMNIGGLDASLYHGTMQYAPLRDEWFYEVIMTDIRVGNDSLGLDCKEYNFDKTIVDSGTTNLRLPVRVFE 316
gi 156379353 163 ---aeptvAGTMVFGEIDEELYKGDLLYTPIVKKWYYEVVITDVAVDGDSLALDCKKYNYDKTIVDSGTTNLRVSEEVFN 239
                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
1YM4_A       259 AAVKSIKAASst--------------------ekFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLmgev---tnqSFRIT 315
gi 112419063 305 AAVKSIKAASst--------------------ekFPDGFWLGEQLVCWQEGTTPWHIFPVISLYLmgev---anqSFKIT 361
gi 41944860  310 AAVKAIEAASst--------------------eqFPSGFWLGEQLVCWQAGTTPWHIFPVISLYLmsen---rnqSFRIS 366
gi 6685260   318 AVVEAVARASli--------------------peFSDGFWTGSQLACWTNSETPWSYFPKISIYLrden---ssrSFRIT 374
gi 33416804  302 AMVDAIVQTSli--------------------qnFNAEFWAGLQLACWDKTQQPWNYFPDISIYLrdtn---tsrSFRLT 358
gi 47208586  255 ALVDAITRSSlvrrrsragltagvdlplicqiqdFSAGFWDGSKLACWMKGETPWRFFPKLSIYLratn---tseSFRIT 331
gi 118083921 300 AVVQAIARTSli--------------------qeFSSGFWSGSQLACWDKTERPWSLFPKLSIYMrden---ssrSFRIS 356
2HIZ_A       306 AAVKSIKAASst--------------------ekFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLmgev---tnqSFRIT 362
2EWY_A       241 AVVEAVARASli--------------------peFSDGFWTGSQLACWTNSETPWSYFPKISIYLrden---ssrSFRIT 297
gi 115693311 317 AITNAIKAHTtkh------------------mpdVPSEFWTGMNLMCPTDSTSPYEPYHWFPTLTldlqstnqgqAFSLV 378
gi 156379353 240 AILDRLRKFDkv--------------------nlIPDDFWYGRQMMCWNYDRTPWEEFPDMSISLlssl--ssskEFRLK 297
                        330       340       350       360       370       380       390
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
Feature 1                                                                                       
1YM4_A       316 ILPQQYLRPVEDvats-qddCYKFAISQSStGTVMGAVIMEGFYVVFDRARKRIGFAVsachvhd-efrtaaVEGPFVT 392
gi 112419063 362 ILPQQYLRPVEDiata-qedCYKFAVSQSTtGTVMGAVIMEGFYVVFDRANKRIGFAVstchvhd-yfrtasVEGPFFA 438
gi 41944860  367 ILPQQYLRPVEDvasa-qedCYKFAVSQSStGTVMGAVIMEGFYVVFERQHKRIGFAVstchvhd-efrtaaVEGPFHG 443
gi 6685260   375 ILPQLYIQPMMGagl--nyeCYRFGISPSTnALVIGATVMEGFYVIFDRAQKRVGFAAspcaeia-gaavseISGPFST 450
gi 33416804  359 LKPQLYIQSVLTfqe--slnCFRFGISQSAsTLVIGATVMEGFYVIFDRAEKRVGFAVsscaevs-gitvseIAGPFGT 434
gi 47208586  332 ILPQLYIQQITDldg--tldCFRFGVSSSVnGLVIGATVMEGFYVVFDRAQRRLGFALstcaasg-glplseIAGPFSA 407
gi 118083921 357 ILPQLYIQPILGige--nlqCYRFGISSSTnALVIGATVMEGFYVIFDRAQRRVGFAVspcaevd-gspvseIEGPFTT 432
2HIZ_A       363 ILPQQYLRPVEDvats-qddCYKFAISQSStGTVMGAVIMEGFYVVFDRARKRIGFAVsachvhd-efrtaaVEGPFVT 439
2EWY_A       298 ILPQLYIQPMMGagl--nyeCYRFGISPSTnALVIGATVMEGFYVIFDRAQKRVGFAAspcaeia-gaavseISGPFST 373
gi 115693311 379 VSPQQYLRRDYDhed--kknCFKFAIAPSTnHAVIGAVIMEGFYVVFDRENKRVGFARstcpgacektgtcvGNSPLIT 455
gi 156379353 298 IPPQLYLRETIEhgpimgqhCYKFAITRAErGTVIGAVIMEGFYVVFDRENVQVGFAAttcggk--epmrylLSSKFYL 374

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