Target Information
| Target General Information | Top | |||||
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| Target ID |
T02484
(Former ID: TTDI01479)
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| Target Name |
Pyridine nucleotide transhydrogenase (NNT)
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| Synonyms |
Nicotinamide nucleotide transhydrogenase; NAD(P) transhydrogenase, mitochondrial
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| Gene Name |
NNT
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane. May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland.
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| UniProt ID | ||||||
| EC Number |
EC 7.1.1.1
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| Sequence |
MANLLKTVVTGCSCPLLSNLGSCKGLRVKKDFLRTFYTHQELWCKAPVKPGIPYKQLTVG
VPKEIFQNEKRVALSPAGVQNLVKQGFNVVVESGAGEASKFSDDHYRVAGAQIQGAKEVL ASDLVVKVRAPMVNPTLGVHEADLLKTSGTLISFIYPAQNPELLNKLSQRKTTVLAMDQV PRVTIAQGYDALSSMANIAGYKAVVLAANHFGRFFTGQITAAGKVPPAKILIVGGGVAGL ASAGAAKSMGAIVRGFDTRAAALEQFKSLGAEPLEVDLKESGEGQGGYAKEMSKEFIEAE MKLFAQQCKEVDILISTALIPGKKAPVLFNKEMIESMKEGSVVVDLAAEAGGNFETTKPG ELYIHKGITHIGYTDLPSRMATQASTLYSNNITKLLKAISPDKDNFYFDVKDDFDFGTMG HVIRGTVVMKDGKVIFPAPTPKNIPQGAPVKQKTVAELEAEKAATITPFRKTMSTASAYT AGLTGILGLGIAAPNLAFSQMVTTFGLAGIVGYHTVWGVTPALHSPLMSVTNAISGLTAV GGLALMGGHLYPSTTSQGLAALAAFISSVNIAGGFLVTQRMLDMFKRPTDPPEYNYLYLL PAGTFVGGYLAALYSGYNIEQIMYLGSGLCCVGALAGLSTQGTARLGNALGMIGVAGGLA ATLGVLKPGPELLAQMSGAMALGGTIGLTIAKRIQISDLPQLVAAFHSLVGLAAVLTCIA EYIIEYPHFATDAAANLTKIVAYLGTYIGGVTFSGSLIAYGKLQGLLKSAPLLLPGRHLL NAGLLAASVGGIIPFMVDPSFTTGITCLGSVSALSAVMGVTLTAAIGGADMPVVITVLNS YSGWALCAEGFLLNNNLLTIVGALIGSSGAILSYIMCVAMNRSLANVILGGYGTTSTAGG KPMEISGTHTEINLDNAIDMIREANSIIITPGYGLCAAKAQYPIADLVKMLTEQGKKVRF GIHPVAGRMPGQLNVLLAEAGVPYDIVLEMDEINHDFPDTDLVLVIGANDTVNSAAQEDP NSIIAGMPVLEVWKSKQVIVMKRSLGVGYAAVDNPIFYKPNTAMLLGDAKKTCDALQAKV RESYQK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| 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: NADP+ | Ligand Info | |||||
| Structure Description | THE CRYSTAL STRUCTURE OF HUMAN TRANSHYDROGENASE DOMAIN III WITH BOUND NADP | PDB:1DJL | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [2] |
| PDB Sequence |
PMEISGTHTE
868 INLDNAIDMI878 REANSIIITP888 GYGLCAAKAQ898 YPIADLVKML908 TEQGKKVRFG 918 IHPVAGRMPG928 QLNVLLAEAG938 VPYDIVLEMD948 EINHDFPDTD958 LVLVIGANDT 968 VNSAAQEDPN978 SIIAGMPVLE988 VWKSKQVIVM998 KRSLGVGYAA1008 VDNPIFYKPN 1018 TAMLLGDAKK1028 TCDALQAKVR1038 ES
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GLY889
3.170
TYR890
2.685
GLY891
3.401
ALA894
4.122
ALA895
3.580
PRO921
4.462
VAL922
2.855
ALA923
3.007
GLY924
3.106
ARG925
2.969
MET926
2.932
PRO927
2.932
GLY964
3.317
ALA965
3.455
ASN966
2.902
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| Ligand Name: NADPH | Ligand Info | |||||
| Structure Description | recombinant human heart transhydrogenase dIII bound with NADPH | PDB:1U31 | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [3] |
| PDB Sequence |
PMEISGTHTE
32 INLDNAIDMI42 REANSIIITP52 GYGLCAAKAQ62 YPIADLVKML72 TEQGKKVRFG 82 IHPVAGRMPG92 QLNVLLAEAG102 VPYDIVLEMD112 EINHDFPDTD122 LVLVIGANDT 132 VNSAAQEDPN142 SIIAGMPVLE152 VWKSKQVIVM162 KRSLGVGYAA172 VDNPIFYKPN 182 TAMLLGDAKK192 TCDALQAKVR202 ES
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GLY53
3.717
TYR54
2.764
GLY55
3.339
ALA58
3.990
ALA59
3.514
PRO85
4.857
VAL86
3.046
ALA87
3.240
GLY88
3.228
ARG89
2.885
MET90
3.336
PRO91
3.202
GLY128
3.171
ALA129
3.486
ASN130
3.391
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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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| Nicotinate and nicotinamide metabolism | hsa00760 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.57E-01 | Radiality | 1.23E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 4.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredox... J Biol Chem. 2014 May 30;289(22):15611-20. | |||||
| REF 2 | The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria. Structure. 2000 Jan 15;8(1):1-12. | |||||
| REF 3 | Active-site conformational changes associated with hydride transfer in proton-translocating transhydrogenase. Biochemistry. 2004 Aug 31;43(34):10952-64. | |||||
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