Target Information
| Target General Information | Top | |||||
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| Target ID |
T98430
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| Target Name |
Alpha-L-iduronidase (IDUA)
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| Gene Name |
IDUA
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lysosomal disease [ICD-11: 5C56] | |||||
| Function |
extracellular exosome, lysosomal lumen, hydrolase activity, hydrolyzing O-glycosyl compounds, L-iduronidase activity, chondroitin sulfate catabolic process, dermatan sulfate catabolic process, disaccharide metabolic process, glycosaminoglycan catabolic process, heparin catabolic process
Click to Show/Hide
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| BioChemical Class |
Glycosyl hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.2.1.76
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| Sequence |
MRPLRPRAALLALLASLLAAPPVAPAEAPHLVHVDAARALWPLRRFWRSTGFCPPLPHSQ
ADQYVLSWDQQLNLAYVGAVPHRGIKQVRTHWLLELVTTRGSTGRGLSYNFTHLDGYLDL LRENQLLPGFELMGSASGHFTDFEDKQQVFEWKDLVSSLARRYIGRYGLAHVSKWNFETW NEPDHHDFDNVSMTMQGFLNYYDACSEGLRAASPALRLGGPGDSFHTPPRSPLSWGLLRH CHDGTNFFTGEAGVRLDYISLHRKGARSSISILEQEKVVAQQIRQLFPKFADTPIYNDEA DPLVGWSLPQPWRADVTYAAMVVKVIAQHQNLLLANTTSAFPYALLSNDNAFLSYHPHPF AQRTLTARFQVNNTRPPHVQLLRKPVLTAMGLLALLDEEQLWAEVSQAGTVLDSNHTVGV LASAHRPQGPADAWRAAVLIYASDDTRAHPNRSVAVTLRLRGVPPGPGLVYVTRYLDNGL CSPDGEWRRLGRPVFPTAEQFRRMRAAEDPVAAAPRPLPAGGRLTLRPALRLPSLLLVHV CARPEKPPGQVTRLRALPLTQGQLVLVWSDEHVGSKCLWTYEIQFSQDGKAYTPVSRKPS TFNLFVFSPDTGAVSGSYRVRALDYWARPGPFSDPVPYLEVPVPRGPPSPGNP 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) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | SB-318 | Drug Info | Phase 1/2 | Mucopolysaccharidosis | [1] | |
| 2 | RGX-111 | Drug Info | Phase 1 | Mucopolysaccharidosis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Replacement | [+] 2 Replacement drugs | + | ||||
| 1 | SB-318 | Drug Info | [1] | |||
| 2 | RGX-111 | Drug Info | [3] | |||
| 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: (1R,2R,3R,4S,6S)-6-amino-2,3,4-trihydroxycyclohexane-1-carboxylic acid | Ligand Info | |||||
| Structure Description | New Irreversible a-l-Iduronidase Inhibitors and Activity-Based Probes | PDB:6I6R | ||||
| Method | X-ray diffraction | Resolution | 2.02 Å | Mutation | No | [4] |
| PDB Sequence |
EAPHLVQVDA
36 ARALWPLRRF46 WRSTGFCPPL56 YVLSWDQQLN73 LAYVGAVPHR83 GIKQVRTHWL 93 LELVTTRGLS108 YNFTHLDGYL118 DLLRENQLLP128 GFELMGSASG138 HFTDFEDKQQ 148 VFEWKDLVSS158 LARRYIGRYG168 LAHVSKWNFE178 TWNEPDHHDF188 DNVSMTMQGF 198 LNYYDACSEG208 LRAASPALRL218 GGPGDSFHTP228 PRSPLSWGLL238 RHCHDGTNFF 248 TGEAGVRLDY258 ISLHRKGARS268 SISILEQEKV278 VAQQIRQLFP288 KFADTPIYND 298 EADPLVGWSL308 PQPWRADVTY318 AAMVVKVIAQ328 HQNLLLAAFP342 YALLSNDNAF 352 LSYHPHPFAQ362 RTLTARFQVN372 NTRPPHVQLL382 RKPVLTAMGL392 LALLDEEQLW 402 AEVSQAGTVL412 DSNHTVGVLA422 SAHRPQGPAD432 AWRAAVLIYA442 SDDTRAHPNR 452 SVAVTLRLRG462 VPPGPGLVYV472 TRYLDNGLCS482 PDGEWRRLGR492 PVFPTAEQFR 502 RMRAAEDPVA512 AAPRPLPAGG522 RLTLRPALRL532 PSLLLVHVCA542 RPEKPPGQVT 552 RLRALPLTQG562 QLVLVWSDEH572 VGSKCLWTYE582 IQFSQAYTPV595 SRKPSTFNLF 605 VFSPDTGAVS615 GSYRVRALDY625 WARPGPFSDP635 VPYLEVP
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| Ligand Name: 2-deoxy-2-fluoro-alpha-L-idopyranuronosyl fluoride | Ligand Info | |||||
| Structure Description | Crystal structure of human alpha-L-iduronidase complex with 2-deoxy-2-fluoro-alpha-L-idopyranosyluronic acid fluoride | PDB:4KH2 | ||||
| Method | X-ray diffraction | Resolution | 2.36 Å | Mutation | No | [5] |
| PDB Sequence |
APHLVQVDAA
37 RALWPLRRFW47 RSTGFCPPYV65 LSWDQQLNLA75 YVGAVPHRGI85 KQVRTHWLLE 95 LVTTLSYNFT112 HLDGYLDLLR122 ENQLLPGFEL132 MGSASGHFTD142 FEDKQQVFEW 152 KDLVSSLARR162 YIGRYGLAHV172 SKWNFETWNE182 PDHHDFDNVS192 MTMQGFLNYY 202 DACSEGLRAA212 SPALRLGGPG222 DSFHTPPRSP232 LSWGLLRHCH242 DGTNFFTGEA 252 GVRLDYISLH262 RKGARSSISI272 LEQEKVVAQQ282 IRQLFPKFAD292 TPIYNDEADP 302 LVGWSLPQPW312 RADVTYAAMV322 VKVIAQHQNL332 LLANTTSAFP342 YALLSNDNAF 352 LSYHPHPFAQ362 RTLTARFQVN372 NTRPPHVQLL382 RKPVLTAMGL392 LALLDEEQLW 402 AEVSQAGTVL412 DSNHTVGVLA422 SAHRPQGPAD432 AWRAAVLIYA442 SDDTRAHPNR 452 SVAVTLRLRG462 VPPGPGLVYV472 TRYLDNGLCS482 PDGEWRRLGR492 PVFPTAEQFR 502 RMRAAEDPVA512 AAPRPLPAGG522 RLTLRPALRL532 PSLLLVHVCA542 RPEKPPGQVT 552 RLRALPLTQG562 QLVLVWSDEH572 VGSKCLWTYE582 IQFSQDYTPV595 SRKPSTFNLF 605 VFSPDTGAVS615 GSYRVRALDY625 WARPGPFSDP635 VPYLE
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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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Glycosaminoglycan degradation | hsa00531 | Affiliated Target |
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| Class: Metabolism => Glycan biosynthesis and metabolism | Pathway Hierarchy | ||
| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 8.09E-04 |
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| Closeness centrality | 9.97E-02 | Radiality | 9.00E+00 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.00E+00 | Topological coefficient | 3.33E-01 | Eccentricity | 15 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | ClinicalTrials.gov (NCT02702115) Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I. U.S. National Institutes of Health. | |||||
| REF 2 | ClinicalTrials.gov (NCT03580083) RGX-111 Gene Therapy in Patients With MPS I. U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of REGENXBIO. | |||||
| REF 4 | New Irreversible Alpha-l-Iduronidase Inhibitors and Activity-Based Probes. Chemistry. 2018 Dec 17;24(71):19081-19088. | |||||
| REF 5 | Insights into mucopolysaccharidosis I from the structure and action of Alpha-L-iduronidase. Nat Chem Biol. 2013 Nov;9(11):739-45. | |||||
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