Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors

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- Beryl(P3)-L-alanyl(P2)-L-argininal(PI) and derivatives thereof) in complex with the uPA proteinase domain. These potent inhibitors are highly selective for uPA. The non-natural D- Beryl 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. (C) 2003 Elsevier Science Ltd. All rights reserved

J. Mol. Biol.

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- Beryl(P3)-L-alanyl(P2)-L-argininal(PI) and derivatives thereof) in complex with the uPA proteinase domain. These potent inhibitors are highly selective for uPA. The non-natural D- Beryl 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. (C) 2003 Elsevier Science Ltd. All rights reserved

Synthesis, Crystal Structure, Spectroscopic and Thermal Properties of a Novel Complex of Hydantoin-5-acetic acid with Co(II)

Yolcu, Zuhal/0000-0001-7761-122X; TAS, MURAT/0000-0002-2879-6501WOS: 000317691200018The complex, tetraaqua bis(hydantoin-5-acetato) cobalt(II) was synthesized by the reaction of hydantoin-5-acetic acid and CoCl2 center dot 6H(2)O presence of NaHCO3. The structure of the complex was determined by X-Ray single crystal data the thermal analyses, FT-IR and magnetic susceptibility data are also presented. The monoclinic crystal of the title compound, [Co(C5H5N2O4)(2)(H2O)(4)], lie across centers of inversion in space group P21/c. The complex features a distorted octahedral [CoO6] coordination with hydantoin-5-acetato and water ligands. The hydantoin-5-acetato anion is bonded to the cobalt(II) ion via its deprotonated carboxylic acid O atom. The complex molecules show three dimensional supramolecular networks by O-H center dot center dot center dot O and N-H center dot center dot center dot O interactions