Target Information
| Target General Information | Top | |||||
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| Target ID |
T72849
(Former ID: TTDR00913)
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| Target Name |
Adipocyte-derived leucine aminopeptidase (ERAP1)
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| Synonyms |
Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator; Puromycin-insensitive leucyl-specific aminopeptidase; PILS-AP; ERAP1; Aminopeptidase PILS; ARTS-1; ALAP; A-LAP
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| Gene Name |
ERAP1
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I- binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulationof blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.11.-
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| Sequence |
MVFLPLKWSLATMSFLLSSLLALLTVSTPSWCQSTEASPKRSDGTPFPWNKIRLPEYVIP
VHYDLLIHANLTTLTFWGTTKVEITASQPTSTIILHSHHLQISRATLRKGAGERLSEEPL QVLEHPRQEQIALLAPEPLLVGLPYTVVIHYAGNLSETFHGFYKSTYRTKEGELRILAST QFEPTAARMAFPCFDEPAFKASFSIKIRREPRHLAISNMPLVKSVTVAEGLIEDHFDVTV KMSTYLVAFIISDFESVSKITKSGVKVSVYAVPDKINQADYALDAAVTLLEFYEDYFSIP YPLPKQDLAAIPDFQSGAMENWGLTTYRESALLFDAEKSSASSKLGITMTVAHELAHQWF GNLVTMEWWNDLWLNEGFAKFMEFVSVSVTHPELKVGDYFFGKCFDAMEVDALNSSHPVS TPVENPAQIREMFDDVSYDKGACILNMLREYLSADAFKSGIVQYLQKHSYKNTKNEDLWD SMASICPTDGVKGMDGFCSRSQHSSSSSHWHQEGVDVKTMMNTWTLQKGFPLITITVRGR NVHMKQEHYMKGSDGAPDTGYLWHVPLTFITSKSDMVHRFLLKTKTDVLILPEEVEWIKF NVGMNGYYIVHYEDDGWDSLTGLLKGTHTAVSSNDRASLINNAFQLVSIGKLSIEKALDL SLYLKHETEIMPVFQGLNELIPMYKLMEKRDMNEVETQFKAFLIRLLRDLIDKQTWTDEG SVSERMLRSQLLLLACVHNYQPCVQRAEGYFRKWKESNGNLSLPVDVTLAVFAVGAQSTE GWDFLYSKYQFSLSSTEKSQIEFALCRTQNKEKLQWLLDESFKGDKIKTQEFPQILTLIG RNPVGYPLAWQFLRKNWNKLVQKFELGSSSIAHMVMGTTNQFSTRTRLEEVKGFFSSLKE NGSQLRCVQQTIETIEENIGWMDKNFDKIRVWLQSEKLERM Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Bestatin | Ligand Info | |||||
| Structure Description | Crystal structure of the soluble domain of human endoplasmic reticulum aminopeptidase 1 ERAP1 | PDB:2YD0 | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [2] |
| PDB Sequence |
PFPWNKIRLP
55 EYVIPVHYDL65 LIHANLTTLT75 FWGTTKVEIT85 ASQPTSTIIL95 HSHHLQISRA 105 TLRKGLSEEP119 LQVLEHPRQE129 QIALLAPEPL139 LVGLPYTVVI149 HYAGNLSETF 159 HGFYKSTYRT169 KEGELRILAS179 TQFEPTAARM189 AFPCFDEPAF199 KASFSIKIRR 209 EPRHLAISNM219 PLVKSVTVAE229 GLIEDHFDVT239 VKMSTYLVAF249 IISDFESVSK 259 ITKSGVKVSV269 YAVPDKINQA279 DYALDAAVTL289 LEFYEDYFSI299 PYPLPKQDLA 309 AIPDFQSGAM319 ENWGLTTYRE329 SALLFDAEKS339 SASSKLGITM349 TVAHELAHQW 359 FGNLVTMEWW369 NDLWLNEGFA379 KFMEFVSVSV389 THPELKVGDY399 FFGKCFDAME 409 VDALNSSHPV419 STPVENPAQI429 REMFDDVSYD439 KGACILNMLR449 EYLSADAFKS 459 GIVQYLQKHS469 YKNTKNEDLW479 DSMASIGVDV517 KTMMNTWTLQ527 KGFPLITITV 537 RGRNVHMKQE547 HYMKGDTGYL562 WHVPLTFITS572 KSDMVHRFLL582 KTKTDVLILP 592 EEVEWIKFNV602 GMNGYYIVHY612 EDDGWDSLTG622 LLKGTHTAVS632 SNDRASLINN 642 AFQLVSIGKL652 SIEKALDLSL662 YLKHETEIMP672 VFQGLNELIP682 MYKLMEKRDM 692 NEVETQFKAF702 LIRLLRDLID712 KQTWTDEGSV722 SERMLRSQLL732 LLACVHNYQP 742 CVQRAEGYFR752 KWKESNGNLS762 LPVDVTLAVF772 AVGAQSTEGW782 DFLYSKYQFS 792 LSSTEKSQIE802 FALCRTQNKE812 KLQWLLDESF822 KGDKIKTQEF832 PQILTLIGRN 842 PVGYPLAWQF852 LRKNWNKLVQ862 KFELGSSSIA872 HMVMGTTNQF882 STRTRLEEVK 892 GFFSSLKENG902 SQLRCVQQTI912 ETIEENIGWM922 DKNFDKIRVW932 LQSEKLER |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Propanoic acid | Ligand Info | |||||
| Structure Description | High-resolution crystal structure of ERAP1 in complex with 15mer phosphinic peptide | PDB:6RYF | ||||
| Method | X-ray diffraction | Resolution | 1.72 Å | Mutation | No | [3] |
| PDB Sequence |
PFPWNKIRLP
55 EYVIPVHYDL65 LIHANLTTLT75 FWGTTKVEIT85 ASQPTSTIIL95 HSHHLQISRA 105 TLRKRLSEEP119 LQVLEHPRQE129 QIALLAPEPL139 LVGLPYTVVI149 HYAGNLSETF 159 HGFYKSTYRT169 KEGELRILAS179 TQFEPTAARM189 AFPCFDEPAF199 KASFSIKIRR 209 EPRHLAISNM219 PLVKSVTVAE229 GLIEDHFDVT239 VKMSTYLVAF249 IISDFESVSK 259 ITKSGVKVSV269 YAVPDKINQA279 DYALDAAVTL289 LEFYEDYFSI299 PYPLPKQDLA 309 AIPDFQSGAM319 ENWGLTTYRE329 SALLFDAEKS339 SASSKLGITM349 TVAHELAHQW 359 FGNLVTMEWW369 NDLWLNEGFA379 KFMEFVSVSV389 THPELKVGDY399 FFGKCFDAME 409 VDALNSSHPV419 STPVENPAQI429 REMFDDVSYD439 KGACILNMLR449 EYLSADAFKS 459 GIVQYLQKHS469 YKNTKNEDLW479 DSMASIVDVK518 TMMNTWTLQK528 GFPLITITVR 538 GRNVHMKQEH548 YMKGDTGYLW563 HVPLTFITSK573 SDMVHRFLLK583 TKTDVLILPE 593 EVEWIKFNVG603 MNGYYIVHYE613 DDGWDSLTGL623 LKGTHTAVSS633 NDRASLINNA 643 FQLVSIGKLS653 IEKALDLSLY663 LKHETEIMPV673 FQGLNELIPM683 YKLMEKRDMN 693 EVETQFKAFL703 IRLLRDLIDK713 QTWTDEGSVS723 ERMLRSQLLL733 LACVHNYQPC 743 VQRAEGYFRK753 WKESNGNLSL763 PVDVTLAVFA773 VGAQSTEGWD783 FLYSKYQFSL 793 SSTEKSQIEF803 ALCRTQNKEK813 LQWLLDESFK823 GDKIKTQEFP833 QILTLIGRNP 843 VGYPLAWQFL853 RKNWNKLVQK863 FELGSSSIAH873 MVMGTTNQFS883 TRTRLEEVKG 893 FFSSLKENGS903 QLRCVQQTIE913 TIEENIGWMD923 KNFDKIRVWL933 QSEKLR |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Similarity Proteins
Human Tissue Distribution
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Cofactor of initiator function (CIF) | 19.704 (40/203) | 5.00E-03 | |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Novel selective inhibitors of aminopeptidases that generate antigenic peptides. Bioorg Med Chem Lett. 2013 Sep 1;23(17):4832-6. | |||||
| REF 2 | Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7745-50. | |||||
| REF 3 | Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1. Proc Natl Acad Sci U S A. 2019 Dec 26;116(52):26709-26716. | |||||
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