Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution.
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.
Hohenester
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E
Department of Crystallography, Birkbeck College, London WC1E 7HX, UK. e.hohenester.cryst.bbk.ac.uk
Sasaki
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T
Olsen
B R
BR
Timpl
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine; D003094:Collagen / Q000737:chemistry*; D043170:Collagen Type XVIII; D018360:Crystallography, X-Ray; D043169:Endostatins; D006493:Heparin / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins
D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D006493:Heparin; D003094:Collagen; D001120:Arginine