Proteins > Urokinase-type plasminogen activator
Page last updated: 2024-08-07 15:32:42
Urokinase-type plasminogen activator
A urokinase-type plasminogen activator that is encoded in the genome of human. [PRO:DNx, UniProtKB:P00749]
Synonyms
U-plasminogen activator;
uPA;
EC 3.4.21.73
Research
Bioassay Publications (49)
| Timeframe | Studies on this Protein(%) | All Drugs % |
|---|
| pre-1990 | 1 (2.04) | 18.7374 |
| 1990's | 3 (6.12) | 18.2507 |
| 2000's | 27 (55.10) | 29.6817 |
| 2010's | 16 (32.65) | 24.3611 |
| 2020's | 2 (4.08) | 2.80 |
Compounds (50)
Drugs with Inhibition Measurements
| Drug | Taxonomy | Measurement | Average (mM) | Bioassay(s) | Publication(s) |
|---|
| gallic acid | Homo sapiens (human) | IC50 | 6.6000 | 1 | 1 |
| 4-aminobenzamidine | Homo sapiens (human) | IC50 | 7.0000 | 1 | 1 |
| 4-iodine-benzo(b)thiophene-2-carboxamidine | Homo sapiens (human) | IC50 | 0.2100 | 1 | 1 |
| 4-iodine-benzo(b)thiophene-2-carboxamidine | Homo sapiens (human) | Ki | 0.2324 | 4 | 4 |
| 5-(n,n-hexamethylene)amiloride | Homo sapiens (human) | IC50 | 2.4000 | 1 | 1 |
| 5-(n,n-hexamethylene)amiloride | Homo sapiens (human) | Ki | 1.3560 | 1 | 1 |
| benzamidine | Homo sapiens (human) | Ki | 180.0000 | 1 | 1 |
| bis(5-amidino-2-benzimidazolyl)methane | Homo sapiens (human) | Ki | 2.3150 | 2 | 2 |
| gabexate | Homo sapiens (human) | IC50 | 0.4310 | 1 | 1 |
| hexachlorophene | Homo sapiens (human) | IC50 | 3.8000 | 1 | 1 |
| netropsin | Homo sapiens (human) | IC50 | 35.0000 | 1 | 2 |
| pentamidine | Homo sapiens (human) | IC50 | 43.3333 | 1 | 3 |
| 1,2,5,8-tetrahydroxy anthraquinone | Homo sapiens (human) | IC50 | 4.4000 | 1 | 1 |
| tranexamic acid | Homo sapiens (human) | Ki | 2,000.0000 | 1 | 1 |
| dibrompropamidine | Homo sapiens (human) | Ki | 1.5700 | 1 | 1 |
| 2-aminobenzimidazole | Homo sapiens (human) | IC50 | 200.0000 | 1 | 1 |
| phenylguanidine | Homo sapiens (human) | IC50 | 20.0000 | 1 | 1 |
| phenylguanidine | Homo sapiens (human) | Ki | 20.6032 | 2 | 2 |
| amiloride | Homo sapiens (human) | IC50 | 22.9633 | 6 | 6 |
| amiloride | Homo sapiens (human) | Ki | 150.8921 | 5 | 7 |
| 2-aminotetralin | Homo sapiens (human) | Ki | 39.8107 | 1 | 1 |
| epigallocatechin gallate | Homo sapiens (human) | IC50 | 0.0910 | 1 | 1 |
| hexamidine | Homo sapiens (human) | Ki | 14.4000 | 1 | 1 |
| amiloride hydrochloride | Homo sapiens (human) | IC50 | 11.0000 | 1 | 1 |
| amiloride hydrochloride | Homo sapiens (human) | Ki | 7.0000 | 1 | 1 |
| sennoside A | Homo sapiens (human) | IC50 | 51.0000 | 1 | 1 |
| 1-aminoisoquinoline | Homo sapiens (human) | Ki | 50.1187 | 1 | 1 |
| sivelestat | Homo sapiens (human) | IC50 | 2.0000 | 1 | 1 |
| 5-amidinoindole | Homo sapiens (human) | Ki | 131.0000 | 1 | 1 |
| 4-guanidinobenzoate | Homo sapiens (human) | IC50 | 342.5000 | 1 | 4 |
| 4-guanidinobenzoate | Homo sapiens (human) | Ki | 744.8660 | 2 | 2 |
| melagatran | Homo sapiens (human) | Ki | 6.3000 | 1 | 1 |
| beta-naphthamidine | Homo sapiens (human) | Ki | 6.0399 | 3 | 3 |
| 3-(3-amino-1,2,4-oxadiazol-5-yl)-5-chloro-2,6-pyrazinediamine | Homo sapiens (human) | IC50 | 1,000.0000 | 1 | 1 |
| 7-amino-3-(2-bromoethoxy)-4-chloroisocoumarin | Homo sapiens (human) | Ki | 12.0000 | 1 | 1 |
| razaxaban | Homo sapiens (human) | Ki | 7.6500 | 2 | 2 |
| actinonin | Homo sapiens (human) | IC50 | 0.1400 | 1 | 1 |
| benzamidine | Homo sapiens (human) | Ki | 200.9294 | 4 | 17 |
| Epigallocatechin 3,5-Digallate | Homo sapiens (human) | IC50 | 0.3300 | 1 | 1 |
| 2-(4-chlorophenyl)guanidine | Homo sapiens (human) | Ki | 6.3843 | 3 | 4 |
| 7-amino-4-chloro-3-(3-isothiureidopropoxy)isocoumarin | Homo sapiens (human) | Ki | 0.0380 | 1 | 1 |
| silybin | Homo sapiens (human) | IC50 | 21.0000 | 1 | 1 |
| quercetin | Homo sapiens (human) | IC50 | 25.4200 | 2 | 5 |
| rutin | Homo sapiens (human) | IC50 | 42.2000 | 1 | 5 |
| b 428 | Homo sapiens (human) | IC50 | 0.3200 | 1 | 1 |
| bms-262084 | Homo sapiens (human) | IC50 | 0.1350 | 1 | 1 |
| upamostat | Homo sapiens (human) | Ki | 0.4100 | 1 | 1 |
| uk-356,202 | Homo sapiens (human) | IC50 | 0.0370 | 1 | 1 |
| uk-356,202 | Homo sapiens (human) | Ki | 0.0303 | 3 | 3 |
| n-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(l)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride | Homo sapiens (human) | IC50 | 0.4100 | 1 | 1 |
| n-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(l)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride | Homo sapiens (human) | Ki | 0.5500 | 5 | 9 |
| dpc 423 | Homo sapiens (human) | Ki | 17.0000 | 1 | 1 |
| a-317567 | Homo sapiens (human) | Ki | 0.0486 | 2 | 2 |
| m-chlorophenylguanidine | Homo sapiens (human) | Ki | 61.7298 | 2 | 2 |
| pf-429242 | Homo sapiens (human) | IC50 | 50.0000 | 1 | 1 |
| grassystatin a | Homo sapiens (human) | IC50 | 10.0000 | 1 | 1 |
| rpx7009 | Homo sapiens (human) | IC50 | 1,000.0000 | 1 | 1 |
Drugs with Activation Measurements
| Drug | Taxonomy | Measurement | Average (mM) | Bioassay(s) | Publication(s) |
|---|
| ko 143 | Homo sapiens (human) | EC50 | 0.0120 | 1 | 1 |
Drugs with Other Measurements
| Drug | Taxonomy | Measurement | Average (mM) | Bioassay(s) | Publication(s) |
|---|
| dpc 423 | Homo sapiens (human) | Activity | 19,000.0000 | 1 | 1 |
Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.Journal of medicinal chemistry, , Feb-25, Volume: 53, Issue:4, 2010
Large-scale application of high-throughput molecular mechanics with Poisson-Boltzmann surface area for routine physics-based scoring of protein-ligand complexes.Journal of medicinal chemistry, , May-28, Volume: 52, Issue:10, 2009
4-Aminoarylguanidine and 4-aminobenzamidine derivatives as potent and selective urokinase-type plasminogen activator inhibitors.Bioorganic & medicinal chemistry letters, , Aug-05, Volume: 12, Issue:15, 2002
Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.Bioorganic & medicinal chemistry letters, , Feb-11, Volume: 12, Issue:3, 2002
Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors.Bioorganic & medicinal chemistry letters, , Apr-09, Volume: 11, Issue:7, 2001
Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.Journal of medicinal chemistry, , May-17, Volume: 50, Issue:10, 2007
Aromatic amidines: comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin.Journal of medicinal chemistry, , Volume: 26, Issue:2, 1983
Disruption of Water Networks is the Cause of Human/Mouse Species Selectivity in Urokinase Plasminogen Activator (uPA) Inhibitors Derived from Hexamethylene Amiloride (HMA).Journal of medicinal chemistry, , 02-10, Volume: 65, Issue:3, 2022
6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease.Bioorganic & medicinal chemistry letters, , 12-15, Volume: 29, Issue:24, 2019
6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.Journal of medicinal chemistry, , 09-27, Volume: 61, Issue:18, 2018
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.Journal of medicinal chemistry, , Dec-10, Volume: 58, Issue:23, 2015
2-Amidino analogs of glycine-amiloride conjugates: inhibitors of urokinase-type plasminogen activator.Bioorganic & medicinal chemistry letters, , Apr-01, Volume: 22, Issue:7, 2012
Large-scale application of high-throughput molecular mechanics with Poisson-Boltzmann surface area for routine physics-based scoring of protein-ligand complexes.Journal of medicinal chemistry, , May-28, Volume: 52, Issue:10, 2009
Development of irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator.Journal of medicinal chemistry, , May-06, Volume: 47, Issue:10, 2004
Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design.Journal of molecular biology, , Aug-11, Volume: 301, Issue:2, 2000
Identification of novel inhibitors of urokinase via NMR-based screening.Journal of medicinal chemistry, , Oct-19, Volume: 43, Issue:21, 2000
Large-scale application of high-throughput molecular mechanics with Poisson-Boltzmann surface area for routine physics-based scoring of protein-ligand complexes.Journal of medicinal chemistry, , May-28, Volume: 52, Issue:10, 2009
Interaction with the S1 beta-pocket of urokinase: 8-heterocycle substituted and 6,8-disubstituted 2-naphthamidine urokinase inhibitors.Bioorganic & medicinal chemistry letters, , Jun-21, Volume: 14, Issue:12, 2004
Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution.Journal of medicinal chemistry, , Jan-15, Volume: 47, Issue:2, 2004
Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.Bioorganic & medicinal chemistry letters, , Nov-01, Volume: 16, Issue:21, 2006
Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors.Bioorganic & medicinal chemistry letters, , Apr-01, Volume: 16, Issue:7, 2006
Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).Journal of molecular biology, , Nov-19, Volume: 344, Issue:2, 2004
A novel serine protease inhibition motif involving a multi-centered short hydrogen bonding network at the active site.Journal of molecular biology, , Apr-13, Volume: 307, Issue:5, 2001
Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design.Journal of molecular biology, , Aug-11, Volume: 301, Issue:2, 2000
Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator.Chemistry & biology, , Volume: 7, Issue:4, 2000
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.Journal of medicinal chemistry, , Dec-10, Volume: 58, Issue:23, 2015
Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.Journal of medicinal chemistry, , Jan-24, Volume: 51, Issue:2, 2008
Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.Journal of medicinal chemistry, , May-17, Volume: 50, Issue:10, 2007
Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines.Bioorganic & medicinal chemistry letters, , Jun-21, Volume: 14, Issue:12, 2004
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.Journal of medicinal chemistry, , Dec-10, Volume: 58, Issue:23, 2015
Synthesis and evaluation of non-basic inhibitors of urokinase-type plasminogen activator (uPA).Bioorganic & medicinal chemistry, , Feb-15, Volume: 20, Issue:4, 2012
Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.Journal of medicinal chemistry, , Jan-24, Volume: 51, Issue:2, 2008
Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.Journal of medicinal chemistry, , Jul-13, Volume: 49, Issue:14, 2006
3-Amidinophenylalanine-based inhibitors of urokinase.Bioorganic & medicinal chemistry letters, , Nov-01, Volume: 9, Issue:21, 1999
Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues.Bioorganic & medicinal chemistry letters, , Mar-01, Volume: 17, Issue:5, 2007
Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor.Journal of medicinal chemistry, , Mar-24, Volume: 48, Issue:6, 2005
Large-scale application of high-throughput molecular mechanics with Poisson-Boltzmann surface area for routine physics-based scoring of protein-ligand complexes.Journal of medicinal chemistry, , May-28, Volume: 52, Issue:10, 2009
Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties.Bioorganic & medicinal chemistry letters, , Jan-03, Volume: 15, Issue:1, 2005
Enables
This protein enables 2 target(s):
| Target | Category | Definition |
|---|
| serine-type endopeptidase activity | molecular function | Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine). [GOC:mah, https://www.ebi.ac.uk/merops/about/glossary.shtml#CATTYPE] |
| protein binding | molecular function | Binding to a protein. [GOC:go_curators] |
Located In
This protein is located in 9 target(s):
| Target | Category | Definition |
|---|
| extracellular region | cellular component | The space external to the outermost structure of a cell. For cells without external protective or external encapsulating structures this refers to space outside of the plasma membrane. This term covers the host cell environment outside an intracellular parasite. [GOC:go_curators] |
| extracellular space | cellular component | That part of a multicellular organism outside the cells proper, usually taken to be outside the plasma membranes, and occupied by fluid. [ISBN:0198547684] |
| plasma membrane | cellular component | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. [ISBN:0716731363] |
| focal adhesion | cellular component | A cell-substrate junction that anchors the cell to the extracellular matrix and that forms a point of termination of actin filaments. In insects focal adhesion has also been referred to as hemi-adherens junction (HAJ). [GOC:aruk, GOC:bc, ISBN:0124325653, ISBN:0815316208, PMID:10419689, PMID:12191915, PMID:15246682, PMID:1643657, PMID:16805308, PMID:19197329, PMID:23033047, PMID:26923917, PMID:28796323, PMID:8314002] |
| external side of plasma membrane | cellular component | The leaflet of the plasma membrane that faces away from the cytoplasm and any proteins embedded or anchored in it or attached to its surface. [GOC:dos, GOC:tb] |
| cell surface | cellular component | The external part of the cell wall and/or plasma membrane. [GOC:jl, GOC:mtg_sensu, GOC:sm] |
| specific granule membrane | cellular component | The lipid bilayer surrounding a specific granule, a granule with a membranous, tubular internal structure, found primarily in mature neutrophil cells. Most are released into the extracellular fluid. Specific granules contain lactoferrin, lysozyme, vitamin B12 binding protein and elastase. [GOC:bf, PMID:7334549] |
| extracellular exosome | cellular component | A vesicle that is released into the extracellular region by fusion of the limiting endosomal membrane of a multivesicular body with the plasma membrane. Extracellular exosomes, also simply called exosomes, have a diameter of about 40-100 nm. [GOC:BHF, GOC:mah, GOC:vesicles, PMID:15908444, PMID:17641064, PMID:19442504, PMID:19498381, PMID:22418571, PMID:24009894] |
| tertiary granule membrane | cellular component | The lipid bilayer surrounding a tertiary granule. [GOC:BHF, GOC:mah, GOC:rl, PMID:12070036] |
Active In
This protein is active in 1 target(s):
| Target | Category | Definition |
|---|
| extracellular space | cellular component | That part of a multicellular organism outside the cells proper, usually taken to be outside the plasma membranes, and occupied by fluid. [ISBN:0198547684] |
Part Of
This protein is part of 3 target(s):
| Target | Category | Definition |
|---|
| serine protease inhibitor complex | cellular component | A heterodimeric protein complex that contains a serine protease inhibitor and a protease; formation of the complex inhibits serine protease activity. [GOC:ans, PMID:6323392] |
| protein complex involved in cell-matrix adhesion | cellular component | Any protein complex that is capable of carrying out some part of the process of cell-matrix adhesion. [GOC:dos] |
| serine-type endopeptidase complex | cellular component | A protein complex which is capable of serine-type endopeptidase activity. [GO_REF:0000088, GOC:bhm, GOC:TermGenie, PMID:1689240] |
Involved In
This protein is involved in 20 target(s):
| Target | Category | Definition |
|---|
| response to hypoxia | biological process | Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level. [GOC:hjd] |
| proteolysis | biological process | The hydrolysis of proteins into smaller polypeptides and/or amino acids by cleavage of their peptide bonds. [GOC:bf, GOC:mah] |
| chemotaxis | biological process | The directed movement of a motile cell or organism, or the directed growth of a cell guided by a specific chemical concentration gradient. Movement may be towards a higher concentration (positive chemotaxis) or towards a lower concentration (negative chemotaxis). [ISBN:0198506732] |
| signal transduction | biological process | The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell. [GOC:go_curators, GOC:mtg_signaling_feb11] |
| blood coagulation | biological process | The sequential process in which the multiple coagulation factors of the blood interact, ultimately resulting in the formation of an insoluble fibrin clot; it may be divided into three stages: stage 1, the formation of intrinsic and extrinsic prothrombin converting principle; stage 2, the formation of thrombin; stage 3, the formation of stable fibrin polymers. [PMID:30700128] |
| regulation of signaling receptor activity | biological process | Any process that modulates the frequency, rate or extent of a signaling receptor activity. Receptor activity is when a molecule combines with an extracellular or intracellular messenger to initiate a change in cell activity. [GOC:dph, GOC:tb] |
| regulation of plasminogen activation | biological process | Any process that modulates the rate, frequency or extent of plasminogen activation. Plasminogen activation is the process in which plasminogen is processed to plasmin. [GOC:BHF, GOC:dph, GOC:tb] |
| negative regulation of plasminogen activation | biological process | Any process that decreases the rate, frequency or extent of plasminogen activation. Plasminogen activation is the process in which plasminogen is processed to plasmin. [GOC:BHF, GOC:dph, GOC:tb] |
| smooth muscle cell migration | biological process | The orderly movement of a smooth muscle cell from one site to another, often during the development of a multicellular organism. [CL:0000192, GOC:mtg_muscle] |
| regulation of smooth muscle cell migration | biological process | Any process that modulates the frequency, rate or extent of smooth muscle cell migration. [CL:0000192, GOC:mtg_muscle] |
| regulation of cell adhesion | biological process | Any process that modulates the frequency, rate or extent of attachment of a cell to another cell or to the extracellular matrix. [GOC:mah] |
| plasminogen activation | biological process | The process in which inactive plasminogen is processed to active plasmin. This process includes cleavage at an internal Arg-Val site to form an N-terminal A-chain and C-terminal B-chain held together by a disulfide bond, and can include further proteolytic cleavage events to remove the preactivation peptide. [PMID:9548733] |
| regulation of cell adhesion mediated by integrin | biological process | Any process that modulates the frequency, rate, or extent of cell adhesion mediated by integrin. [GOC:add] |
| urokinase plasminogen activator signaling pathway | biological process | The series of molecular signals initiated by urokinase plasminogen activator binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:gap, PMID:9417082] |
| regulation of cell population proliferation | biological process | Any process that modulates the frequency, rate or extent of cell proliferation. [GOC:jl] |
| fibrinolysis | biological process | A process that solubilizes fibrin in the bloodstream of a multicellular organism, chiefly by the proteolytic action of plasmin. [GOC:jl, PMID:15842654] |
| regulation of fibrinolysis | biological process | Any process that modulates the frequency, rate or extent of fibrinolysis, an ongoing process that solubilizes fibrin, resulting in the removal of small blood clots. [GOC:ai] |
| negative regulation of fibrinolysis | biological process | Any process that stops, prevents, or reduces the frequency, rate or extent of fibrinolysis, an ongoing process that solubilizes fibrin, resulting in the removal of small blood clots. [GOC:ai] |
| regulation of wound healing | biological process | Any process that modulates the rate, frequency, or extent of the series of events that restore integrity to a damaged tissue, following an injury. [GOC:BHF, GOC:dph] |
| regulation of smooth muscle cell-matrix adhesion | biological process | Any process that modulates the frequency, rate or extent of smooth muscle cell-matrix adhesion. [GOC:BHF] |