Target Information
| Target General Information | Top | |||||
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| Target ID |
T72335
(Former ID: TTDR01027)
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| Target Name |
Bacterial Lethal factor (Bact lef)
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| Synonyms |
lef; Anthrax lethal toxin endopeptidase component; Anthrax lethal factor; ALF
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| Gene Name |
Bact lef
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Sepsis [ICD-11: 1G40-1G41] | |||||
| Function |
One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.83
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| Sequence |
MNIKKEFIKVISMSCLVTAITLSGPVFIPLVQGAGGHGDVGMHVKEKEKNKDENKRKDEE
RNKTQEEHLKEIMKHIVKIEVKGEEAVKKEAAEKLLEKVPSDVLEMYKAIGGKIYIVDGD ITKHISLEALSEDKKKIKDIYGKDALLHEHYVYAKEGYEPVLVIQSSEDYVENTEKALNV YYEIGKILSRDILSKINQPYQKFLDVLNTIKNASDSDGQDLLFTNQLKEHPTDFSVEFLE QNSNEVQEVFAKAFAYYIEPQHRDVLQLYAPEAFNYMDKFNEQEINLSLEELKDQRMLAR YEKWEKIKQHYQHWSDSLSEEGRGLLKKLQIPIEPKKDDIIHSLSQEEKELLKRIQIDSS DFLSTEEKEFLKKLQIDIRDSLSEEEKELLNRIQVDSSNPLSEKEKEFLKKLKLDIQPYD INQRLQDTGGLIDSPSINLDVRKQYKRDIQNIDALLHQSIGSTLYNKIYLYENMNINNLT ATLGADLVDSTDNTKINRGIFNEFKKNFKYSISSNYMIVDINERPALDNERLKWRIQLSP DTRAGYLENGKLILQRNIGLEIKDVQIIKQSEKEYIRIDAKVVPKSKIDTKIQEAQLNIN QEWNKALGLPKYTKLITFNVHNRYASNIVESAYLILNEWKNNIQSDLIKKVTNYLVDGNG RFVFTDITLPNIAEQYTHQDEIYEQVHSKGLYVPESRSILLHGPSKGVELRNDSEGFIHE FGHAVDDYAGYLLDKNQSDLVTNSKKFIDIFKEEGSNLTSYGRTNEAEFFAEAFRLMHST DHAERLKVQKNAPKTFQFINDQIKFIINS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | IQ-DAA | Drug Info | Phase 1 | Bacillus anthracis infection | [2] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | GM6001 | Drug Info | Discontinued in Phase 2 | Corneal ulcer | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | IQ-DAA | Drug Info | [1] | |||
| Inhibitor | [+] 13 Inhibitor drugs | + | ||||
| 1 | GM6001 | Drug Info | [4] | |||
| 2 | 3-(2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid | Drug Info | [5] | |||
| 3 | Bisindolylmaleimide-I | Drug Info | [6] | |||
| 4 | GNF-PF-600 | Drug Info | [7] | |||
| 5 | MMI270 | Drug Info | [8] | |||
| 6 | N,N'-Bis(4-Amino-2-Methylquinolin-6-Yl)Urea | Drug Info | [4] | |||
| 7 | N-(3,4,5-trihydroxyphenethyl)oleamide | Drug Info | [9] | |||
| 8 | N-(3,4-dihydroxybenzyl)oleamide | Drug Info | [10] | |||
| 9 | N-(Sulfanylacetyl)Tyrosylprolylmethioninamide | Drug Info | [4] | |||
| 10 | N-hydroxy-4-(2-oleamidoethyl)benzamide | Drug Info | [9] | |||
| 11 | N-hydroxy-4-(oleamidomethyl)benzamide | Drug Info | [10] | |||
| 12 | N-oleoyl-dopamine | Drug Info | [9] | |||
| 13 | NSC-622445 | Drug Info | [5] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: N,N'-Bis(4-Amino-2-Methylquinolin-6-Yl)Urea | Ligand Info | |||||
| Structure Description | Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155 | PDB:1PWP | ||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | No | [11] |
| PDB Sequence |
KTQEEHLKEI
39 MKHIVKIEVK49 GEEAVKKEAA59 EKLLEKVPSD69 VLEMYKAIGG79 KIYIVDGDIT 89 KHISLEALSE99 DKKKIKDIYG109 KDALLHEHYV119 YAKEGYEPVL129 VIQSSEDYVE 139 NTEKALNVYY149 EIGKILSRDI159 LSKINQPYQK169 FLDVLNTIKN179 ASDSDGQDLL 189 FTNQLKEHPT199 DFSVEFLEQN209 SNEVQEVFAK219 AFAYYIEPQH229 RDVLQLYAPE 239 AFNYMDKFNE249 QEINLSLEEL259 KDQRMLSRYE269 KWEKIKQHYQ279 HWSDSLSEEG 289 RGLLKKLQIP299 IEPKKDDIIH309 SLSQEEKELL319 KRIQIDSSDF329 LSTEEKEFLK 339 KLQIDIRDSL349 SNPLSEKEKE374 FLKKLKLDIQ384 PYDINQRLQD394 TGGLIDSPSI 404 NLDVRKQYKR414 DIQNIDALLH424 QSIGSTLYNK434 IYLYENMNIN444 NLTATLGADL 454 VDSTDNTKIN464 RGIFNEFKKN474 FKYSISSNYM484 IVDINERPAL494 DNERLKWRIQ 504 LSPDTRAGYL514 ENGKLILQRN524 IGLEIKDVQI534 IKQSEKEYIR544 IDAKVVPKSK 554 IDTKIQEAQL564 NINQEWNKAL574 GLPKYTKLIT584 FNVHNRYASN594 IVESAYLILN 604 EWKNNIQSDL614 IKKVTNYLVD624 GNGRFVFTDI634 TLPNIAEQYT644 HQDEIYEQVH 654 SKGLYVPESR664 SILLHGPSKG674 VELRNDSEGF684 IHEFGHAVDD694 YAGYLLDKNQ 704 SDLVTNSKKF714 IDIFKEEGSN724 LTSYGRTNEA734 EFFAEAFRLM744 HSTDHAERLK 754 VQKNAPKTFQ764 FINDQIKFII774 NS
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| Ligand Name: N-(Sulfanylacetyl)Tyrosylprolylmethioninamide | Ligand Info | |||||
| Structure Description | Crystal structure of Anthrax Lethal Factor complexed with Thioacetyl-Tyr-Pro-Met-Amide, a metal-chelating peptidyl small molecule inhibitor | PDB:1PWQ | ||||
| Method | X-ray diffraction | Resolution | 3.52 Å | Mutation | No | [12] |
| PDB Sequence |
ERNKTQEEHL
36 KEIMKHIVKI46 EVKGEEAVKK56 EAAEKLLEKV66 PSDVLEMYKA76 IGGKIYIVDG 86 DITKHISLEA96 LSEDKKKIKD106 IYGKDALLHE116 HYVYAKEGYE126 PVLVIQSSED 136 YVENTEKALN146 VYYEIGKILS156 RDILSKINQP166 YQKFLDVLNT176 IKNASDSDGQ 186 DLLFTNQLKE196 HPTDFSVEFL206 EQNSNEVQEV216 FAKAFAYYIE226 PQHRDVLQLY 236 APEAFNYMDK246 FNEQEINLSL256 EELKDQRMLS266 RYEKWEKIKQ276 HYQHWSDSLS 286 EEGRGLLKKL296 QIPIEPKKDD306 IIHSLSQEEK316 ELLKRIQIDS326 SDFLSTEEKE 336 FLKKLQIDIR346 SNPLSEKEKE374 FLKKLKLDIQ384 PYDINQRLQD394 TGGLIDSPSI 404 NLDVRKQYKR414 DIQNIDALLH424 QSIGSTLYNK434 IYLYENMNIN444 NLTATLGADL 454 VDSTDNTKIN464 RGIFNEFKKN474 FKYSISSNYM484 IVDINERPAL494 DNERLKWRIQ 504 LSPDTRAGYL514 ENGKLILQRN524 IGLEIKDVQI534 IKQSEKEYIR544 IDAKVVPKSK 554 IDTKIQEAQL564 NINQEWNKAL574 GLPKYTKLIT584 FNVHNRYASN594 IVESAYLILN 604 EWKNNIQSDL614 IKKVTNYLVD624 GNGRFVFTDI634 TLPNIAEQYT644 HQDEIYEQVH 654 SKGLYVPESR664 SILLHGPSKG674 VELRNDSEGF684 IHEFGHAVDD694 YAGYLLDKNQ 704 SDLVTNSKKF714 IDIFKEEGSN724 LTSYGRTNEA734 EFFAEAFRLM744 HSTDHAERLK 754 VQKNAPKTFQ764 FINDQIKFII774 NS
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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 Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Cellular roles of Anthrax toxin | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Uptake and function of anthrax toxins | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax.Future Microbiol.2009 Feb;4(1):35-43. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020942) | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387) | |||||
| REF 4 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 5 | Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening. J Med Chem. 2006 Aug 24;49(17):5232-44. | |||||
| REF 6 | Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother. 2007 Jul;51(7):2403-11. | |||||
| REF 7 | Anthrax lethal factor protease inhibitors: synthesis, SAR, and structure-based 3D QSAR studies. J Med Chem. 2006 Jan 12;49(1):27-30. | |||||
| REF 8 | The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection. Bioorg Med Chem Lett. 2006 Feb 15;16(4):964-8. | |||||
| REF 9 | Inhibitors of anthrax lethal factor. Bioorg Med Chem Lett. 2007 Aug 15;17(16):4575-8. | |||||
| REF 10 | Inhibitors of anthrax lethal factor based upon N-oleoyldopamine. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2467-70. | |||||
| REF 11 | Identification of small molecule inhibitors of anthrax lethal factor. Nat Struct Mol Biol. 2004 Jan;11(1):67-72. | |||||
| REF 12 | The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat Struct Mol Biol. 2004 Jan;11(1):60-6. | |||||
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