Target Information
| Target General Information | Top | |||||
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| Target ID |
T15514
(Former ID: TTDR00269)
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| Target Name |
Hepatocyte nuclear factor 4-alpha (HNF4A)
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| Synonyms |
Transcription factor HNF-4; Transcription factor 14; TCF14; TCF-14; Nuclear receptor subfamily 2 group A member 1; NR2A1; HNF4; HNF-4-alpha
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| Gene Name |
HNF4A
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Activates the transcription of CYP2C38. Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells. Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes.
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGNDTSPSEGTNLNAPNSLGVSALC
AICGDRATGKHYGASSCDGCKGFFRRSVRKNHMYSCRFSRQCVVDKDKRNQCRYCRLKKC FRAGMKKEAVQNERDRISTRRSSYEDSSLPSINALLQAEVLSRQITSPVSGINGDIRAKK IASIADVCESMKEQLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHLLLGATKRSMVFK DVLLLGNDYIVPRHCPELAEMSRVSIRILDELVLPFQELQIDDNEYAYLKAIIFFDPDAK GLSDPGKIKRLRSQVQVSLEDYINDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQFIKL FGMAKIDNLLQEMLLGGSPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNGQMCEW PRPRGQAATPETPQPSPPGGSGSEPYKLLPGAVATIVKPLSAIPQPTITKQEVI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T49J7I | |||||
| 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: Lauric acid | Ligand Info | |||||
| Structure Description | HNF4alpha in complex with the corepressor EBP1 fragment | PDB:6CHT | ||||
| Method | X-ray diffraction | Resolution | 3.17 Å | Mutation | No | [4] |
| PDB Sequence |
SINALLQAEV
151 LAKKIASIAD177 VCESMKEQLL187 VLVEWAKYIP197 AFCELPLDDQ207 VALLRAHAGE 217 HLLLGATKRS227 MVFKDVLLLG237 NDYIVPRHCP247 ELAEMSRVSI257 RILDELVLPF 267 QELQIDDNEY277 AYLKAIIFFD287 PDAKGLSDPG297 KIKRLRSQVQ307 VSLEDYINDR 317 QYDSRGRFGE327 LLLLLPTLQS337 ITWQMIEQIQ347 FIKLFGMAKI357 DNLLQEMLLG 367
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| Ligand Name: Myristic acid | Ligand Info | |||||
| Structure Description | Crystal structure of HNF4a LBD in complex with the ligand and the coactivator SRC-1 peptide | PDB:1PZL | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [5] |
| PDB Sequence |
LASLPSINAL
146 LQAEVLSRQI156 TNGDIRAKKI172 ASIADVCESM182 KEQLLVLVEW192 AKYIPAFCEL 202 PLDDQVALLR212 AHAGEHLLLG222 ATKRSMVFKD232 VLLLGNDYIV242 PRHCPELAEM 252 SRVSIRILDE262 LVLPFQELQI272 DDNEYAYLKA282 IIFFDPDAKG292 LSDPGKIKRL 302 RSQVQVSLED312 YINDRQYDSR322 GRFGELLLLL332 PTLQSITWQM342 IEQIQFIKLF 352 GMAKIDNLLQ362 EMLLGGS
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VAL178
3.896
SER181
2.488
MET182
3.837
GLN185
3.560
LEU219
3.841
LEU220
4.035
GLY222
4.574
ALA223
3.586
ARG226
2.396
LEU234
3.954
LEU235
4.986
LEU236
3.601
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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).
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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| AMPK signaling pathway | hsa04152 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 5.88E-05 |
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| Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 5.83E-01 |
| Neighborhood connectivity | 8.08E+01 | Topological coefficient | 1.69E-01 | Eccentricity | 11 |
| 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-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | AMPK signaling pathway | |||||
| 2 | Maturity onset diabetes of the young | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | Regulation of nuclear SMAD2/3 signaling | |||||
| 2 | FOXA2 and FOXA3 transcription factor networks | |||||
| 3 | HIF-1-alpha transcription factor network | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Nuclear Receptor transcription pathway | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Mesodermal Commitment Pathway | |||||
| 2 | Integrated Pancreatic Cancer Pathway | |||||
| 3 | Nuclear Receptors | |||||
| 4 | AMPK Signaling | |||||
| References | Top | |||||
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| REF 1 | HNF4alpha antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol. 2012 Jul 27;19(7):806-18. | |||||
| REF 2 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 3 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 4 | ErbB3-binding protein 1 (EBP1) represses HNF4Alpha-mediated transcription and insulin secretion in pancreatic beta-cells. J Biol Chem. 2019 Sep 20;294(38):13983-13994. | |||||
| REF 5 | Structural basis for HNF-4alpha activation by ligand and coactivator binding. J Biol Chem. 2004 May 28;279(22):23311-6. | |||||
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