Hohenester E, Sasaki T, Olsen B R, Timpl R
Department of Crystallography, Birkbeck College, London WC1E 7HX, UK. e.hohenester.cryst.bbk.ac.uk
EMBO J. 1998 Mar 16;17(6):1656-64. doi: 10.1093/emboj/17.6.1656.
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.
许多细胞外蛋白含有潜在的血管生成抑制剂。内皮抑素是胶原蛋白XVIII的一个20 kDa C端蛋白水解片段，能有效抑制内皮细胞增殖和血管生成。用内皮抑素治疗实验性癌症可导致肿瘤休眠，且不会诱导耐药性。我们已表达重组小鼠内皮抑素，并以1.5埃的分辨率确定了其晶体结构。该结构揭示了一种紧密折叠，与C型凝集素碳水化合物识别结构域和透明质酸结合Link模块有较远的关系。内皮抑素对肝素的高亲和力可通过由11个精氨酸残基形成的广泛碱性区域来解释。内皮抑素可能通过与参与生长因子信号传导的硫酸乙酰肝素蛋白聚糖结合来抑制血管生成。
