1W12

UROKINASE TYPE PLASMINOGEN ACTIVATOR

1W12 の概要

• エントリーDOI: 10.2210/pdb1w12/pdb
• 関連するPDBエントリー: 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 1W10 1W11 1W13 1W14
• 分子名称: UROKINASE-TYPE PLASMINOGEN ACTIVATOR, N-((1S)-4-{[AMINO(IMINO)METHYL]AMINO}-1-FORMYLBUTYL)-2-{(3R)-3-[(BENZYLSULFONYL)AMINO]-2-OXO-5-PHENYL-2,3-DIHYDRO-1H-1,4-BENZODIAZEPIN-1-YL}ACETAMIDE (3 entities in total)
• 機能のキーワード: urokinase, hydrolase, plasminogen activator
• 由来する生物種: HOMO SAPIENS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28450.38

構造登録者

Jacob, U. (登録日: 2004-06-15, 公開日: 2008-05-20, 最終更新日: 2019-05-22)

主引用文献

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., 328:109-, 2003

PubMed Abstract: 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.

PubMed: 12684001
DOI: 10.1016/S0022-2836(03)00267-5

実験手法

X-RAY DIFFRACTION (2.4 Å)