| Structural highlights
1w10 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | ,
| | Related: | 1c5w, 1c5x, 1c5y, 1c5z, 1ejn, 1f5k, 1f5l, 1f92, 1fv9, 1gi7, 1gi8, 1gi9, 1gj7, 1gj8, 1gj9, 1gja, 1gjb, 1gjc, 1gjd, 1kdu, 1lmw, 1o3p, 1owd, 1owe, 1owh, 1owi, 1owj, 1owk, 1sqa, 1sqo, 1sqt, 1urk, 1w0z, 1w11, 1w12, 1w13, 1w14 |
| Activity: | U-plasminogen activator, with EC number 3.4.21.73 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[UROK_HUMAN] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.[1]
Function
[UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Urokinase type plasminogen activator (uPA), a trypsin-like serine proteinase, plays an important role in normal tissue re-modelling, cell adhesion, and cell motility. In addition, studies utilizing normal animals and potent, selective uPA inhibitors or genetically modified mice that lack functional uPA genes have demonstrated that uPA can significantly enhance tumor initiation, growth, progression and metastasis, strongly suggesting that this enzyme may be a promising anti-cancer target. We have investigated the structure-activity relationship (SAR) of peptidomimetic inhibitors of uPA and solved high resolution X-ray structures of key, lead small molecule inhibitors (e.g. phenethylsulfonamidino(P4)-D-seryl(P3)-L-alanyl(P2)-L-argininal(P1) and derivatives thereof) in complex with the uPA proteinase domain. These potent inhibitors are highly selective for uPA. The non-natural D-seryl residue present at the P3 position in these inhibitors contributes substantially to both potency and selectivity because, due to its D-configuration, its side-chain binds in the S4 pocket to interact with the uPA unique residues Leu97b and His99. Additional potency and selectivity can be achieved by optimizing the inhibitor P4 residue to bind a pocket, known as S1sub or S1beta, that is adjacent to the primary specificity pocket of uPA.
Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors.,Zeslawska E, Jacob U, Schweinitz A, Coombs G, Bode W, Madison E J Mol Biol. 2003 Apr 18;328(1):109-18. PMID:12684001[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Paterson AD, Rommens JM, Bharaj B, Blavignac J, Wong I, Diamandis M, Waye JS, Rivard GE, Hayward CP. Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene. Blood. 2010 Feb 11;115(6):1264-6. doi: 10.1182/blood-2009-07-233965. Epub 2009, Dec 9. PMID:20007542 doi:10.1182/blood-2009-07-233965
- ↑ Zeslawska E, Jacob U, Schweinitz A, Coombs G, Bode W, Madison E. Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors. J Mol Biol. 2003 Apr 18;328(1):109-18. PMID:12684001
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