Target Information
Target General Information | Top | |||||
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Target ID |
T94201
(Former ID: TTDI03560)
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Target Name |
SRSF protein kinase 1 (SRPK1)
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Synonyms |
Serine/arginine-rich protein-specific kinase 1; SR-protein-specific kinase 1; SFRS protein kinase 1
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Gene Name |
SRPK1
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Target Type |
Preclinical target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Retinopathy [ICD-11: 9B71] | |||||
Function |
Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.11.1
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Sequence |
MERKVLALQARKKRTKAKKDKAQRKSETQHRGSAPHSESDLPEQEEEILGSDDDEQEDPN
DYCKGGYHLVKIGDLFNGRYHVIRKLGWGHFSTVWLSWDIQGKKFVAMKVVKSAEHYTET ALDEIRLLKSVRNSDPNDPNREMVVQLLDDFKISGVNGTHICMVFEVLGHHLLKWIIKSN YQGLPLPCVKKIIQQVLQGLDYLHTKCRIIHTDIKPENILLSVNEQYIRRLAAEATEWQR SGAPPPSGSAVSTAPQPKPADKMSKNKKKKLKKKQKRQAELLEKRMQEIEEMEKESGPGQ KRPNKQEESESPVERPLKENPPNKMTQEKLEESSTIGQDQTLMERDTEGGAAEINCNGVI EVINYTQNSNNETLRHKEDLHNANDCDVQNLNQESSFLSSQNGDSSTSQETDSCTPITSE VSDTMVCQSSSTVGQSFSEQHISQLQESIRAEIPCEDEQEQEHNGPLDNKGKSTAGNFLV NPLEPKNAEKLKVKIADLGNACWVHKHFTEDIQTRQYRSLEVLIGSGYNTPADIWSTACM AFELATGDYLFEPHSGEEYTRDEDHIALIIELLGKVPRKLIVAGKYSKEFFTKKGDLKHI TKLKPWGLFEVLVEKYEWSQEEAAGFTDFLLPMLELIPEKRATAAECLRHPWLNS 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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Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
1 | SPHINX31 | Drug Info | Preclinical | Wet age-related macular degeneration | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 5 Inhibitor drugs | + | ||||
1 | Sphinx | Drug Info | [3] | |||
2 | SPHINX scaffold, 3 | Drug Info | [3] | |||
3 | ZINC959121 | Drug Info | [3] | |||
4 | SPHINX31 | Drug Info | [2] | |||
5 | PMID15925511C13 | Drug Info | [1] |
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: L-alanine | Ligand Info | |||||
Structure Description | Crystal structure of SR protein kinase 1 complexed to its substrate ASF/SF2 | PDB:3BEG | ||||
Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | No | [4] |
PDB Sequence |
LVKIGDLFNG
78 RYHVIRKLGW88 GHFSTVWLSW98 DIQGKKFVAM108 KVVKSAEHYT118 ETALDEIRLL 128 KSVRNSDPND138 PNREMVVQLL148 DDFKISGVNG158 THICMVFEVL168 GHHLLKWIIK 178 SNYQGLPLPC188 VKKIIQQVLQ198 GLDYLHTKCR208 IIHTDIKPEN218 ILLSVNEQYI 228 RRLAAEAAGN477 FLVNPLEPKN487 AEKLKVKIAD497 LGNACWVHKH507 FTEDIQTRQY 517 RSLEVLIGSG527 YNTPADIWST537 ACMAFELATG547 DYLFEPHSGE557 EYTRDEDHIA 567 LIIELLGKVP577 RKLIVAGKYS587 KEFFTKKGDL597 KHITKLKPWG607 LFEVLVEKYE 617 WSQEEAAGFT627 DFLLPMLELI637 PEKRATAAEC647 LRHPWLNS
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Ligand Name: Alectinib | Ligand Info | |||||
Structure Description | SRPK1 in complex with Alectinib | PDB:5XV7 | ||||
Method | X-ray diffraction | Resolution | 2.32 Å | Mutation | No | [5] |
PDB Sequence |
YHLVKIGDLF
76 NGRYHVIRKL86 GWGHFSTVWL96 SWDIQGKKFV106 AMKVVKSAEH116 YTETALDEIR 126 LLKSVRNSDP136 NDPNREMVVQ146 LLDDFKISGV156 NGTHIVMVFE166 VLGHHLLKWI 176 IKSNYQGLPL186 PCVKKIIQQV196 LQGLDYLHTK206 CRIIHTDIKP216 ENILLSVNEQ 226 YIRRLAAEAT236 ENFLVNPLEP485 KNAEKLKVKI495 ADLGNACWVH505 KHFTEDIQTR 515 QYRSLEVLIG525 SGYNTPADIW535 STACMAFELA545 TGDYLFEPHS555 GEEYTRDEDH 565 IALIIELLGK575 VPRKLIVAGK585 YSKEFFTKKG595 DLKHITKLKP605 WGLFEVLVEK 615 YEWSQEEAAG625 FTDFLLPMLE635 LIPEKRATAA645 ECLRHPWLNS655 |
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ARG84
3.653
LEU86
3.093
GLY87
3.903
VAL94
3.870
LEU96
4.931
ALA107
3.678
LYS109
4.886
GLU124
4.658
VAL145
4.135
PHE165
3.320
GLU166
4.081
VAL167
3.549
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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).
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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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 | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 2.50E-06 |
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Closeness centrality | 1.76E-01 | Radiality | 1.29E+01 | Clustering coefficient | 5.71E-01 |
Neighborhood connectivity | 2.23E+01 | Topological coefficient | 2.86E-01 | Eccentricity | 14 |
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 Regulators | Top | |||||
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Target-interacting Proteins |
References | Top | |||||
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REF 1 | Synthesis of selective SRPK-1 inhibitors: novel tricyclic quinoxaline derivatives. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3241-6. | |||||
REF 2 | Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018 May;17(5):353-377. | |||||
REF 3 | Piperazine derivatives for treating disorders. US9695160. | |||||
REF 4 | A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1. Mol Cell. 2008 Mar 14;29(5):563-76. | |||||
REF 5 | SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform. Cell Chem Biol. 2018 Apr 19;25(4):460-470.e6. |
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