1hpj

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1hpj, 12 NMR models ()
Activity: Plasmin, with EC number 3.4.21.7
Related: 1hpk
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

SOLUTION NMR STRUCTURE OF THE HUMAN PLASMINOGEN KRINGLE 1 DOMAIN COMPLEXED WITH 6-AMINOHEXANOIC ACID AT PH 5.3, 310K, DERIVED FROM RANDOMLY GENERATED STRUCTURES USING SIMULATED ANNEALING, 12 STRUCTURES

Publication Abstract from PubMed

The solution structure of the human plasminogen kringle 1 domain complexed to the antifibrinolytic drug 6-aminohexanoic acid (epsilon Ahx) was obtained on the basis of 1H-NMR spectroscopic data and dynamical simulated annealing calculations. Two sets of structures were derived starting from (a) random coil conformations and (b) the (mutated) crystallographic structure of the homologous prothrombin kringle 1. The two sets display essentially the same backbone folding (pairwise root-mean-square deviation, 0.15 nm) indicating that, regardless of the initial structure, the data is sufficient to locate a conformation corresponding to an essentially unique energy minimum. The conformations of residues connected to prolines were localized to energetically preferred regions of the Ramachandran map. The Pro30 peptide bond is proposed to be cis. The ligand-binding site of the kringle 1 is a shallow cavity composed of Pro33, Phe36, Trp62, Tyr64, Tyr72 and Tyr74. Doubly charged anionic and cationic centers configured by the side chains of Asp55 and Asp57, and Arg34 and Arg71, respectively, contribute to anchoring the zwitterionic epsilon Ahx molecule at the binding site. The ligand exhibits closer contacts with the kringle anionic centers (approximately 0.35 nm average O...H distance between the Asp55/Asp57 carboxylate and ligand amino groups) than with the cationic ones (approximately 0.52 nm closest O...H distances between the ligand carboxylate and the Arg34/Arg71 guanidino groups). The epsilon Ahx hydrocarbon chain rests flanked by Pro33, Tyr64, Tyr72 and Tyr74 on one side and Phe36 on the other. Dipolar (Overhauser) connectivities indicate that the ligand aliphatic moiety establishes close contacts with the Phe36 and Trp62 aromatic rings. The computed structure suggests that the epsilon Ahx molecule adopts a kinked conformation when complexed to kringle 1, effectively shortening its dipole length to approximately 0.65 nm.

Solution structure of the epsilon-aminohexanoic acid complex of human plasminogen kringle 1., Rejante MR, Llinas M, Eur J Biochem. 1994 May 1;221(3):939-49. PMID:8181476

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

1hpj is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA.

See Also

Reference

  • Rejante MR, Llinas M. Solution structure of the epsilon-aminohexanoic acid complex of human plasminogen kringle 1. Eur J Biochem. 1994 May 1;221(3):939-49. PMID:8181476
  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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