Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site
Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site
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DOI：
10.1073/pnas.94.14.7192
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发表时间：
1997-07-08
影响因子：
11.1
通讯作者：
DeVos, AM
中科院分区：
文献类型：
--
作者：
Muller, YA;Li, B;DeVos, AM
血管内皮生长因子（VEGF）是半胱氨酸结生长因子家族的同二聚体成员，与血小板衍生生长因子（PDGF）和转化生长因子β 2 （tgf - β）具有有限的序列同源性。我们在2.5埃的分辨率下确定了它的晶体结构，并通过突变分析确定了它的激酶结构域受体（KDR）结合位点。总的来说，VEGF单体类似于PDGF，但其n端段是螺旋状的，而不是延长的。VEGF的二聚化模式与PDGF相似，与tgf - β有很大不同。VEGF的突变分析显示，KDR的对称结合位点位于VEGF同型二聚体的每一个极点。每个位点包含两个功能性的“热点”，这些“热点”由跨亚基界面呈现的结合决定子组成。两个最重要的决定因子位于PDGF和tgf - β中保守的短三链薄片上最大的热点内。两种受体阻断抗体结合表位的功能分析揭示了每个KDR结合热点附近不同的结合决定因子。
Vascular endothelial growth factor (VEGF) is a homodimeric member of the cystine knot family of growth factors, with limited sequence homology to platelet-derived growth factor (PDGF) and transforming growth factor beta 2 (TGF-beta). We have determined its crystal structure at a resolution of 2.5 Angstrom, and identified its kinase domain receptor (KDR) binding site using mutational analysis. Overall, the VEGF monomer resembles that of PDGF, but its N-terminal segment is helical rather than extended. The dimerization mode of VEGF is similar to that of PDGF and very different from that of TGF-beta. Mutational analysis of VEGF reveals that symmetrical binding sites for KDR are located at each pole of the VEGF homodimer. Each site contains two functional ''hot spots'' composed of binding determinants presented across the subunit interface. The two most important determinants are located within the largest hot spot on a short, three-stranded sheet that is conserved in PDGF and TGF-beta. Functional analysis of the binding epitopes for two receptor-blocking antibodies reveal different binding determinants near each of the KDR binding hot spots.