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PDBsum entry 1koe
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Angiogenesis inhibitor PDB id
1koe

 

 

 

 

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Contents
Protein chain
172 a.a. *
Waters ×83
* Residue conservation analysis
PDB id:
1koe
Name: Angiogenesis inhibitor
Title: Endostatin
Structure: Endostatin. Chain: a. Fragment: c-terminal 184 residues of alpha1 chain of collagen xviii. Engineered: yes. Other_details: n-terminal ala-pro-leu-ala sequence introduced by the cloning process
Source: Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: 293 ebna cells. Organ: kidney. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: 293 ebna cells
Resolution:
1.50Å     R-factor:   0.190     R-free:   0.224
Authors: E.Hohenester,T.Sasaki,B.R.Olsen,R.Timpl
Key ref:
E.Hohenester et al. (1998). Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J, 17, 1656-1664. PubMed id: 9501087 DOI: 10.1093/emboj/17.6.1656
Date:
22-Jan-98     Release date:   16-Feb-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P39061  (COIA1_MOUSE) -  Collagen alpha-1(XVIII) chain from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1774 a.a.
172 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1093/emboj/17.6.1656 EMBO J 17:1656-1664 (1998)
PubMed id: 9501087  
 
 
Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution.
E.Hohenester, T.Sasaki, B.R.Olsen, R.Timpl.
 
  ABSTRACT  
 
A number of extracellular proteins contain cryptic inhibitors of angiogenesis. Endostatin is a 20 kDa C-terminal proteolytic fragment of collagen XVIII that potently inhibits endothelial cell proliferation and angiogenesis. Therapy of experimental cancer with endostatin leads to tumour dormancy and does not induce resistance. We have expressed recombinant mouse endostatin and determined its crystal structure at 1.5 A resolution. The structure reveals a compact fold distantly related to the C-type lectin carbohydrate recognition domain and the hyaluronan-binding Link module. The high affinity of endostatin for heparin is explained by the presence of an extensive basic patch formed by 11 arginine residues. Endostatin may inhibit angiogenesis by binding to the heparan sulphate proteoglycans involved in growth factor signalling.
 
  Selected figure(s)  
 
Figure 2.
Figure 2 Stereo view of the final 2F[obs]-F[calc] map at 1.5 Å resolution. The region around -strand P is shown, with the disulphide bond between Cys164 and Cys304 in the centre. The map is contoured at the 1.5 level and is shown with the refined model superimposed. The figure was made with BOBSCRIPT (R.Esnouf, personal communication), a modified version of MOLSCRIPT (Kraulis, 1991). 		Figure 5.
Figure 5 Electrostatic surface representation (Nicholls, 1992) of endostatin. The two views of the endostatin surface are related by a rotation of 130° about the horizontal axis. Blue indicates regions of positive potential and red regions of negative potential, at the 5 kT/e level. The N- and the C-termini are indicated; basic residues and the solvent-exposed side chains of Phe162 and Phe165 are labelled in yellow and white, respectively. The hatched area corresponds to the oligosaccharide-binding site of C-type lectin CRDs.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1998, 17, 1656-1664) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  19390655 O.Suzuki, E.Kague, K.Bagatini, H.Tu, R.Heljasvaara, L.Carvalhaes, E.Gava, G.de Oliveira, P.Godoi, G.Oliva, G.Kitten, T.Pihlajaniemi, and M.R.Passos-Bueno (2009).
Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome.
  Mol Vis, 15, 801-809.  
19472178 Y.Fu, H.Tang, Y.Huang, N.Song, and Y.Luo (2009).
Unraveling the mysteries of endostatin.
  IUBMB Life, 61, 613-626.  
18463113 H.Tan, S.Yang, Y.Feng, C.Liu, J.Cao, G.Mu, and F.Wang (2008).
Characterization and secondary structure analysis of endostatin covalently modified by polyethylene glycol and low molecular weight heparin.
  J Biochem, 144, 207-213.  
17447877 A.V.Digtyar, N.V.Pozdnyakova, N.B.Feldman, S.V.Lutsenko, and S.E.Severin (2007).
Endostatin: current concepts about its biological role and mechanisms of action.
  Biochemistry (Mosc), 72, 235-246.  
18000555 B.Stevenson, H.A.Choy, M.Pinne, M.L.Rotondi, M.C.Miller, E.Demoll, P.Kraiczy, A.E.Cooley, T.P.Creamer, M.A.Suchard, C.A.Brissette, A.Verma, and D.A.Haake (2007).
Leptospira interrogans Endostatin-Like Outer Membrane Proteins Bind Host Fibronectin, Laminin and Regulators of Complement.
  PLoS ONE, 2, e1188.  
17587451 S.P.Balasubramanian, S.S.Cross, J.Globe, A.Cox, N.J.Brown, and M.W.Reed (2007).
Endostatin gene variation and protein levels in breast cancer susceptibility and severity.
  BMC Cancer, 7, 107.  
16481316 A.Clamp, F.H.Blackhall, A.Henrioud, G.C.Jayson, K.Javaherian, J.Esko, J.T.Gallagher, and C.L.Merry (2006).
The morphogenic properties of oligomeric endostatin are dependent on cell surface heparan sulfate.
  J Biol Chem, 281, 14813-14822.  
17142959 H.Nagasawa, Y.Uto, K.L.Kirk, and H.Hori (2006).
Design of hypoxia-targeting drugs as new cancer chemotherapeutics.
  Biol Pharm Bull, 29, 2335-2342.  
17082192 J.Khoshnoodi, J.P.Cartailler, K.Alvares, A.Veis, and B.G.Hudson (2006).
Molecular recognition in the assembly of collagens: terminal noncollagenous domains are key recognition modules in the formation of triple helical protomers.
  J Biol Chem, 281, 38117-38121.  
16403516 J.Pilch, C.M.Franzin, L.M.Knowles, F.J.Ferrer, F.M.Marassi, and E.Ruoslahti (2006).
The anti-angiogenic peptide anginex disrupts the cell membrane.
  J Mol Biol, 356, 876-885.  
16336259 A.N.Zelensky, and J.E.Gready (2005).
The C-type lectin-like domain superfamily.
  FEBS J, 272, 6179-6217.  
15653078 G.Bix, and R.V.Iozzo (2005).
Matrix revolutions: "tails" of basement-membrane components with angiostatic functions.
  Trends Cell Biol, 15, 52-60.  
15634676 H.Zhou, W.Wang, and Y.Luo (2005).
Contributions of disulfide bonds in a nested pattern to the structure, stability, and biological functions of endostatin.
  J Biol Chem, 280, 11303-11312.  
16869777 M.A.Grant, and R.Kalluri (2005).
Structural basis for the functions of endogenous angiogenesis inhibitors.
  Cold Spring Harb Symp Quant Biol, 70, 399-410.  
15614762 N.Rychkova, S.Stahl, S.Gaetzner, and U.Felbor (2005).
Non-heparan sulfate-binding interactions of endostatin/collagen XVIII in murine development.
  Dev Dyn, 232, 399-407.  
16064139 R.V.Iozzo (2005).
Basement membrane proteoglycans: from cellar to ceiling.
  Nat Rev Mol Cell Biol, 6, 646-656.  
16115201 S.Stahl, S.Gaetzner, T.D.Mueller, and U.Felbor (2005).
Endostatin phenylalanines 31 and 34 define a receptor binding site.
  Genes Cells, 10, 929-939.  
16020281 Y.S.Wang, W.Eichler, U.Friedrichs, Y.Yafai, S.Hoffmann, T.Yasukawa, Y.N.Hui, and P.Wiedemann (2005).
Impact of endostatin on bFGF-induced proliferation, migration, and matrix metalloproteinase-2 expression/secretion of bovine choroidal endothelial cells.
  Curr Eye Res, 30, 479-489.  
15012971 A.Morabito, R.Sarmiento, P.Bonginelli, and G.Gasparini (2004).
Antiangiogenic strategies, compounds, and early clinical results in breast cancer.
  Crit Rev Oncol Hematol, 49, 91.  
15188432 A.Schmidt, D.Wenzel, I.Ferring, S.Kazemi, T.Sasaki, J.Hescheler, R.Timpl, K.Addicks, B.K.Fleischmann, and W.Bloch (2004).
Influence of endostatin on embryonic vasculo- and angiogenesis.
  Dev Dyn, 230, 468-480.  
14735467 N.Liu, X.M.Xu, J.Chen, L.Wang, S.Yang, C.B.Underhill, and L.Zhang (2004).
Hyaluronan-binding peptide can inhibit tumor growth by interacting with Bcl-2.
  Int J Cancer, 109, 49-57.  
14973128 S.A.Wickström, K.Alitalo, and J.Keski-Oja (2004).
An endostatin-derived peptide interacts with integrins and regulates actin cytoskeleton and migration of endothelial cells.
  J Biol Chem, 279, 20178-20185.  
14585835 S.Ricard-Blum, O.Féraud, H.Lortat-Jacob, A.Rencurosi, N.Fukai, F.Dkhissi, D.Vittet, A.Imberty, B.R.Olsen, and M.van der Rest (2004).
Characterization of endostatin binding to heparin and heparan sulfate by surface plasmon resonance and molecular modeling: role of divalent cations.
  J Biol Chem, 279, 2927-2936.  
15148373 Y.Yu, K.S.Moulton, M.K.Khan, S.Vineberg, E.Boye, V.M.Davis, P.E.O'Donnell, J.Bischoff, and D.S.Milstone (2004).
E-selectin is required for the antiangiogenic activity of endostatin.
  Proc Natl Acad Sci U S A, 101, 8005-8010.  
  14532152 A.E.Koch (2003).
Angiogenesis as a target in rheumatoid arthritis.
  Ann Rheum Dis, 62, ii60-ii67.  
12866057 A.N.Zelensky, and J.E.Gready (2003).
Comparative analysis of structural properties of the C-type-lectin-like domain (CTLD).
  Proteins, 52, 466-477.  
  12741078 E.J.Kucharz, A.Kotulska, M.Kopeć, B.Stawiarska-Pieta, and R.Pieczyrak (2003).
Serum level of the circulating angiogenesis inhibitor endostatin in patients with hyperthyroidism or hypothyroidism.
  Wien Klin Wochenschr, 115, 179-181.  
12869217 F.Dkhissi, H.Lu, C.Soria, P.Opolon, F.Griscelli, H.Liu, P.Khattar, Z.Mishal, M.Perricaudet, and H.Li (2003).
Endostatin exhibits a direct antitumor effect in addition to its antiangiogenic activity in colon cancer cells.
  Hum Gene Ther, 14, 997.  
  14514474 H.UrbaÅ„ska-RyÅ›, and T.Robak (2003).
High serum level of endostatin in multiple myeloma at diagnosis but not in the plateau phase after treatment.
  Mediators Inflamm, 12, 229-235.  
12947097 K.H.Mayo, R.P.Dings, C.Flader, I.Nesmelova, B.Hargittai, D.W.van der Schaft, L.I.van Eijk, D.Walek, J.Haseman, T.R.Hoye, and A.W.Griffioen (2003).
Design of a partial peptide mimetic of anginex with antiangiogenic and anticancer activity.
  J Biol Chem, 278, 45746-45752.  
12778132 R.Kalluri (2003).
Basement membranes: structure, assembly and role in tumour angiogenesis.
  Nat Rev Cancer, 3, 422-433.  
12837607 S.Schenk, and V.Quaranta (2003).
Tales from the crypt[ic] sites of the extracellular matrix.
  Trends Cell Biol, 13, 366-375.  
12657135 D.R.Sorensen, and T.A.Read (2002).
Delivery of endostatin in experimental cancer therapy.
  Int J Exp Pathol, 83, 265-274.  
11772427 D.R.Sorensen, T.A.Read, T.Porwol, B.R.Olsen, R.Timpl, T.Sasaki, P.O.Iversen, H.B.Benestad, B.K.Sim, and R.Bjerkvig (2002).
Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma.
  Neuro Oncol, 4, 1-8.  
12456637 J.Kreuger, T.Matsumoto, M.Vanwildemeersch, T.Sasaki, R.Timpl, L.Claesson-Welsh, D.Spillmann, and U.Lindahl (2002).
Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function.
  EMBO J, 21, 6303-6311.  
12237301 K.Javaherian, S.Y.Park, W.F.Pickl, K.R.LaMontagne, R.T.Sjin, S.Gillies, and K.M.Lo (2002).
Laminin modulates morphogenic properties of the collagen XVIII endostatin domain.
  J Biol Chem, 277, 45211-45218.  
11970952 M.Sundaramoorthy, M.Meiyappan, P.Todd, and B.G.Hudson (2002).
Crystal structure of NC1 domains. Structural basis for type IV collagen assembly in basement membranes.
  J Biol Chem, 277, 31142-31153.
PDB code: 1m3d
12376553 N.Ortega, and Z.Werb (2002).
New functional roles for non-collagenous domains of basement membrane collagens.
  J Cell Sci, 115, 4201-4214.  
11445906 H.John, and W.G.Forssmann (2001).
Determination of the disulfide bond pattern of the endogenous and recombinant angiogenesis inhibitor endostatin by mass spectrometry.
  Rapid Commun Mass Spectrom, 15, 1222-1228.  
11336704 S.A.Karumanchi, V.Jha, R.Ramchandran, A.Karihaloo, L.Tsiokas, B.Chan, M.Dhanabal, J.I.Hanai, G.Venkataraman, Z.Shriver, N.Keiser, R.Kalluri, H.Zeng, D.Mukhopadhyay, R.L.Chen, A.D.Lander, K.Hagihara, Y.Yamaguchi, R.Sasisekharan, L.Cantley, and V.P.Sukhatme (2001).
Cell surface glypicans are low-affinity endostatin receptors.
  Mol Cell, 7, 811-822.  
10758166 B.V.Sauter, O.Martinet, W.J.Zhang, J.Mandeli, and S.L.Woo (2000).
Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.
  Proc Natl Acad Sci U S A, 97, 4802-4807.  
11020798 C.T.Chen, J.Lin, Q.Li, S.S.Phipps, J.L.Jakubczak, D.A.Stewart, Y.Skripchenko, S.Forry-Schaudies, J.Wood, C.Schnell, and P.L.Hallenbeck (2000).
Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin.
  Hum Gene Ther, 11, 1983-1996.  
11089829 D.Ratel, V.Nasser, I.Dupré, A.L.Benabid, and F.Berger (2000).
Antibodies to endostatin in a multifocal glioblastoma patient.
  Lancet, 356, 1656-1657.  
10813833 H.Zhang, K.Huang, Z.Li, L.Banerjei, K.E.Fisher, N.V.Grishin, E.Eisenstein, and O.Herzberg (2000).
Crystal structure of YbaK protein from Haemophilus influenzae (HI1434) at 1.8 A resolution: functional implications.
  Proteins, 40, 86-97.
PDB codes: 1dbu 1dbx
10971740 K.Norrby (2000).
2.5 kDa and 5.0 kDa heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF165-mediated mammalian angiogenesis.
  Int J Exp Pathol, 81, 191-198.  
10799835 M.Hagedorn, and A.Bikfalvi (2000).
Target molecules for anti-angiogenic therapy: from basic research to clinical trials.
  Crit Rev Oncol Hematol, 34, 89.  
10885579 U.K.Zatterstrom, U.Felbor, N.Fukai, and B.R.Olsen (2000).
Collagen XVIII/endostatin structure and functional role in angiogenesis.
  Cell Struct Funct, 25, 97.  
10051458 B.Clément, O.Musso, J.Liétard, and N.Théret (1999).
Homeostatic control of angiogenesis: A newly identified function of the liver?
  Hepatology, 29, 621-623.  
10508765 K.Drickamer (1999).
C-type lectin-like domains.
  Curr Opin Struct Biol, 9, 585-590.  
10607664 M.Vijayan, and N.Chandra (1999).
Lectins.
  Curr Opin Struct Biol, 9, 707-714.  
10449407 N.Yamaguchi, B.Anand-Apte, M.Lee, T.Sasaki, N.Fukai, R.Shapiro, I.Que, C.Lowik, R.Timpl, and B.R.Olsen (1999).
Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding.
  EMBO J, 18, 4414-4423.  
10562536 T.Sasaki, H.Larsson, J.Kreuger, M.Salmivirta, L.Claesson-Welsh, U.Lindahl, E.Hohenester, and R.Timpl (1999).
Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin.
  EMBO J, 18, 6240-6248.  
  10393839 Z.Chang, A.Choon, and A.Friedl (1999).
Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding.
  Am J Pathol, 155, 71-76.  
9620709 A.L.Harris (1998).
Are angiostatin and endostatin cures for cancer?
  Lancet, 351, 1598-1599.  
9788974 B.Sharma, M.Handler, I.Eichstetter, J.M.Whitelock, M.A.Nugent, and R.V.Iozzo (1998).
Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo.
  J Clin Invest, 102, 1599-1608.  
9687493 T.Sasaki, N.Fukai, K.Mann, W.Göhring, B.R.Olsen, and R.Timpl (1998).
Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin.
  EMBO J, 17, 4249-4256.  
9724722 Y.H.Ding, K.Javaherian, K.M.Lo, R.Chopra, T.Boehm, J.Lanciotti, B.A.Harris, Y.Li, R.Shapiro, E.Hohenester, R.Timpl, J.Folkman, and D.C.Wiley (1998).
Zinc-dependent dimers observed in crystals of human endostatin.
  Proc Natl Acad Sci U S A, 95, 10443-10448.
PDB code: 1bnl
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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