U-plasminogen activator

1C5W, 1C5X, 1C5Y, 1C5Z, 1EJN, 1F5K, 1F5L, 1F92, 1FV9, 1GI7, 1GI8, 1GI9, 1GJ7, 1GJ8, 1GJ9, 1GJA, 1GJB, 1GJC, 1GJD, 1KDU, 1LMW, 1O3P, 1O5A, 1O5B, 1O5C, 1OWD, 1OWE, 1OWH, 1OWI, 1OWJ, 1OWK, 1SC8, 1SQA, 1SQO, 1SQT, 1U6Q, 1VJA, 1W0Z, 1W10, 1W11, 1W12, 1W13, 1W14, 2FD6, 2NWN, 2O8T, 2O8U, 2O8W, 2R2W, 2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, 2VIW, 2VNT, 3BT1, 3BT2, 3IG6, 3KGP, 3KHV, 3KID, 3M61, 3MHW, 3MWI, 3OX7, 3OY5, 3OY6, 3QN7, 3U73, 4DVA, 4DW2, 4FU7, 4FU8, 4FU9, 4FUB, 4FUC, 4FUD, 4FUE, 4FUF, 4FUG, 4FUH, 4FUI, 4FUJ, 4GLY, 4H42, 4JK5, 4JK6, 1URK, 4JNI, 4JNL, 4K24, 4MNV, 4MNW, 4MNX, 4MNY, 4OS1, 4OS2, 4OS4, 4OS5, 4OS6, 4OS7, 4X1N, 4X1Q, 4X1R, 4ZHL, 4ZHM, 4X0W, 4X1P, 4XSK, 4X1S, 5HGG, 4ZKO, 2I9B, 4ZKR, 4ZKS, 2I9A, 4ZKN532818792ENSG00000122861ENSMUSG00000021822P00749P06869NM_001145031NM_002658NM_001319191NM_008873NP_001138503NP_001306120NP_002649NP_032899Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.1c5w: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR1c5x: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR1c5y: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR1c5z: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR1ejn: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN INHIBITOR COMPLEX1f5k: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-BENZAMIDINE COMPLEX1f5l: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-AMILORIDE COMPLEX1f92: UROKINASE PLASMINOGEN ACTIVATOR B CHAIN-UKI-1D COMPLEX1fv9: Crystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazole1gi7: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE1gi8: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE1gi9: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE1gj7: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gj8: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gj9: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gja: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gjb: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gjc: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1gjd: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS1kdu: SEQUENTIAL 1H NMR ASSIGNMENTS AND SECONDARY STRUCTURE OF THE KRINGLE DOMAIN FROM UROKINASE1lmw: LMW U-PA STRUCTURE COMPLEXED WITH EGRCMK (GLU-GLY-ARG CHLOROMETHYL KETONE)1o3p: Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors1o5a: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)1o5b: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)1o5c: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)1owd: Substituted 2-Naphthamidine inhibitors of urokinase1owe: Substituted 2-Naphthamidine inhibitors of urokinase1owh: Substituted 2-Naphthamidine Inhibitors of Urokinase1owi: Substituted 2-Naphthamidine Inhibitors of Urokinase1owj: Substituted 2-Naphthamidine Inhibitors of Urokinase1owk: Substituted 2-Naphthamidine Inhibitors of Urokinase1sc8: Urokinase Plasminogen Activator B-Chain-J435 Complex1sqa: Substituted 2-Naphthamidine Inhibitors of Urokinase1sqo: Substituted 2-Naphthamidine Inhibitors of Urokinase1sqt: Substituted 2-Naphthamidine Inhibitors of Urokinase1u6q: Substituted 2-Naphthamadine inhibitors of Urokinase1urk: SOLUTION STRUCTURE OF THE AMINO TERMINAL FRAGMENT OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR1vj9: Urokinase Plasminogen Activator B-Chain-JT464 Complex1vja: Urokinase Plasminogen Activator B-Chain-JT464 Complex2fd6: Structure of Human Urokinase Plasminogen Activator in Complex with Urokinase Receptor and an anti-upar antibody at 1.9 A2i9a: Crystal structure of the free aminoterminal fragment of urokinase type plasminogen activator (ATF)2i9b: Crystal structure of ATF-urokinase receptor complex Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression. Urokinase is encoded in humans by the PLAU gene, which stands for 'plasminogen activator, urokinase'. The same symbol represents the gene in other animal species. The PLAU gene encodes a serine protease (EC 3.4.21.73) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor. Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond. The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor. uPa also interacts with protein C inhibitor. Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents. However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways. As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials. Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer. Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance). Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment. Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, peripheral arterial occlusive disease, pulmonary embolism, acute myocardial infarction (AMI, heart attack), and occluded dialysis cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with recombinant tissue plasminogen activator (e.g., alteplase) as a thrombolytic drug.