1ki0

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1ki0, resolution 1.75Å ()
Ligands:
Activity: Plasmin, with EC number 3.4.21.7
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

The X-ray Structure of Human Angiostatin

Publication Abstract from PubMed

Angiogenesis inhibitors have gained much public attention recently as anti-cancer agents and several are currently in clinical trials, including angiostatin (Phase I, Thomas Jefferson University Hospital, Philadelphia, PA). We report here the bowl-shaped structure of angiostatin kringles 1-3, the first multi-kringle structure to be determined. All three kringle lysine-binding sites contain a bound bicine molecule of crystallization while the former of kringle 2 and kringle 3 are cofacial. Moreover, the separation of the kringle 2 and kringle 3 lysiner binding sites is sufficient to accommodate the alpha-helix of the 30 residue peptide VEK-30 found in the kringle 2/VEK-30 complex. Together the three kringles produce a central cavity suggestive of a unique domain where they may function in concert.

The X-ray crystallographic structure of the angiogenesis inhibitor angiostatin., Abad MC, Arni RK, Grella DK, Castellino FJ, Tulinsky A, Geiger JH, J Mol Biol. 2002 May 10;318(4):1009-17. PMID:12054798

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[PLMN_HUMAN] Defects in PLG are the cause of plasminogen deficiency (PLGD) [MIM:217090]. PLGD is characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa.[1][2][3][4][5][6][7][8]

Function

[PLMN_HUMAN] Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells.[9] Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.[10]

About this Structure

1ki0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Abad MC, Arni RK, Grella DK, Castellino FJ, Tulinsky A, Geiger JH. The X-ray crystallographic structure of the angiogenesis inhibitor angiostatin. J Mol Biol. 2002 May 10;318(4):1009-17. PMID:12054798 doi:10.1016/S0022-2836(02)00211-5
  1. Ichinose A, Espling ES, Takamatsu J, Saito H, Shinmyozu K, Maruyama I, Petersen TE, Davie EW. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):115-9. PMID:1986355
  2. Azuma H, Uno Y, Shigekiyo T, Saito S. Congenital plasminogen deficiency caused by a Ser572 to Pro mutation. Blood. 1993 Jul 15;82(2):475-80. PMID:8392398
  3. Miyata T, Iwanaga S, Sakata Y, Aoki N. Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6132-6. PMID:6216475
  4. Miyata T, Iwanaga S, Sakata Y, Aoki N, Takamatsu J, Kamiya T. Plasminogens Tochigi II and Nagoya: two additional molecular defects with Ala-600----Thr replacement found in plasmin light chain variants. J Biochem. 1984 Aug;96(2):277-87. PMID:6238949
  5. Kikuchi S, Yamanouchi Y, Li L, Kobayashi K, Ijima H, Miyazaki R, Tsuchiya S, Hamaguchi H. Plasminogen with type-I mutation is polymorphic in the Japanese population. Hum Genet. 1992 Sep-Oct;90(1-2):7-11. PMID:1427790
  6. Schuster V, Mingers AM, Seidenspinner S, Nussgens Z, Pukrop T, Kreth HW. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood. 1997 Aug 1;90(3):958-66. PMID:9242524
  7. Higuchi Y, Furihata K, Ueno I, Ishikawa S, Okumura N, Tozuka M, Sakurai N. Plasminogen Kanagawa-I, a novel missense mutation, is caused by the amino acid substitution G732R. Br J Haematol. 1998 Dec;103(3):867-70. PMID:9858247
  8. Schuster V, Seidenspinner S, Zeitler P, Escher C, Pleyer U, Bernauer W, Stiehm ER, Isenberg S, Seregard S, Olsson T, Mingers AM, Schambeck C, Kreth HW. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood. 1999 May 15;93(10):3457-66. PMID:10233898
  9. Rossignol P, Ho-Tin-Noe B, Vranckx R, Bouton MC, Meilhac O, Lijnen HR, Guillin MC, Michel JB, Angles-Cano E. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem. 2004 Mar 12;279(11):10346-56. Epub 2003 Dec 29. PMID:14699093 doi:10.1074/jbc.M310964200
  10. Rossignol P, Ho-Tin-Noe B, Vranckx R, Bouton MC, Meilhac O, Lijnen HR, Guillin MC, Michel JB, Angles-Cano E. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem. 2004 Mar 12;279(11):10346-56. Epub 2003 Dec 29. PMID:14699093 doi:10.1074/jbc.M310964200

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