Target Information
| Target General Information | Top | |||||
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| Target ID |
T76059
(Former ID: TTDC00307)
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| Target Name |
FK506-binding protein 1A (FKBP1A)
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| Synonyms |
Rotamase; Peptidyl-prolyl cis-trans isomerase FKBP1A; PPIase FKBP1A; Immunophillin FKBP; Immunophilin FKBP12; FKBP12; FKBP1; FKBP-1A; FKBP-12; FK-binding protein 12; Calstabin-1; 12 kDa FKBP; 12 kDa FK506-binding protein
Click to Show/Hide
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| Gene Name |
FKBP1A
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Parkinsonism [ICD-11: 8A00] | |||||
| 2 | Pruritus [ICD-11: EC90] | |||||
| 3 | Transplant rejection [ICD-11: NE84] | |||||
| Function |
Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand.
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| BioChemical Class |
Cis-trans-isomerase
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| UniProt ID | ||||||
| EC Number |
EC 5.2.1.8
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| Sequence |
MGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGW
EEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLE 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) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | GPI-1485 | Drug Info | Phase 2 | Parkinson disease | [2] | |
| 2 | SDZ-281-240 | Drug Info | Phase 2 | Pruritus | [3] | |
| 3 | AP1903 | Drug Info | Phase 1/2 | Transplant rejection | [4] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Gpi-1046 | Drug Info | Terminated | Parkinson disease | [5] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Binder | [+] 1 Binder drugs | + | ||||
| 1 | GPI-1485 | Drug Info | [6] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | SDZ-281-240 | Drug Info | [3] | |||
| 2 | AP1903 | Drug Info | [7], [8] | |||
| Inhibitor | [+] 8 Inhibitor drugs | + | ||||
| 1 | Gpi-1046 | Drug Info | [9] | |||
| 2 | 4-Hydroxy-2-Butanone | Drug Info | [10] | |||
| 3 | FKB-001 | Drug Info | [10] | |||
| 4 | Heptyl-Beta-D-Glucopyranoside | Drug Info | [11] | |||
| 5 | L-709,587 | Drug Info | [10] | |||
| 6 | Methyl Methylsulfinylmethyl Sulfide | Drug Info | [10] | |||
| 7 | MYRISTIC ACID | Drug Info | [9] | |||
| 8 | Rapamycin Immunosuppressant Drug | Drug Info | [10] | |||
| 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: Tacrolimus | Ligand Info | |||||
| Structure Description | FK506 BINDING PROTEIN FKBP MUTANT R42K/H87V COMPLEX WITH IMMUNOSUPPRESSANT FK506 | PDB:1BKF | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [12] |
| PDB Sequence |
GVQVETISPG
10 DGRTFPKRGQ20 TCVVHYTGML30 EDGKKFDSSR40 DKNKPFKFML50 GKQEVIRGWE 60 EGVAQMSVGQ70 RAKLTISPDY80 AYGATGVPGI90 IPPHATLVFD100 VELLKLE |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Sirolimus | Ligand Info | |||||
| Structure Description | ATOMIC STRUCTURE OF THE RAPAMYCIN HUMAN IMMUNOPHILIN FKBP-12 COMPLEX | PDB:1FKB | ||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [13] |
| PDB Sequence |
GVQVETISPG
10 DGRTFPKRGQ20 TCVVHYTGML30 EDGKKFDSSR40 DRNKPFKFML50 GKQEVIRGWE 60 EGVAQMSVGQ70 RAKLTISPDY80 AYGATGHPGI90 IPPHATLVFD100 VELLKLE |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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).
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
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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| Degree | 15 | Degree centrality | 1.61E-03 | Betweenness centrality | 2.13E-03 |
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| Closeness centrality | 2.29E-01 | Radiality | 1.40E+01 | Clustering coefficient | 1.14E-01 |
| Neighborhood connectivity | 2.50E+01 | Topological coefficient | 1.07E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Neural roles of immunophilins and their ligands. Mol Neurobiol. 1997 Oct;15(2):223-39. | |||||
| REF 2 | Emerging drugs for Parkinson's disease. Expert Opin Emerg Drugs. 2006 Sep;11(3):403-17. | |||||
| REF 3 | Clearing of psoriasis by a novel immunosuppressive macrolide. J Invest Dermatol. 1996 Apr;106(4):701-10. | |||||
| REF 4 | ClinicalTrials.gov (NCT01744223) Safety Study of Gene Modified Donor T-cells Following Partially Mismatched Stem Cell Transplant. U.S. National Institutes of Health. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008349) | |||||
| REF 6 | Drugs used to treat Parkinson's disease, present status and future directions. CNS Neurol Disord Drug Targets. 2008 Oct;7(4):321-42. | |||||
| REF 7 | Using gene transfer to circumvent off-target effects. Gene Ther. 2008 May;15(10):759-64. | |||||
| REF 8 | Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42. | |||||
| REF 9 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 10 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 11 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
| REF 12 | Conformation of Fk506 in X-Ray Structures of its Complexes with Human Recombinant Fkbp12 Mutants | |||||
| REF 13 | Atomic Structure of the Rapamycin Human Immunophilin Fkbp-12 Complex | |||||
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