Leonard Philip, Scotney Pierre D, Jabeen Talat, Iyer Shalini, Fabri Louis J, Nash Andrew D, Acharya K Ravi
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
J Mol Biol. 2008 Dec 31;384(5):1203-17. doi: 10.1016/j.jmb.2008.09.076. Epub 2008 Oct 9.
Vascular endothelial growth factor (VEGF) B effects blood vessel formation by binding to VEGF receptor 1. To study the specifics of the biological profile of VEGF-B in both physiological and pathological angiogenesis, a neutralising anti-VEGF-B antibody (2H10) that functions by inhibiting the binding of VEGF-B to VEGF receptor 1 was developed. Here, we present the structural features of the 'highly ordered' interaction of the Fab fragment of this antibody (Fab-2H10) with VEGF-B. Two molecules of Fab-2H10 bind to symmetrical binding sites located at each pole of the VEGF-B homodimer, giving a unique U-shaped topology to the complex that has not been previously observed in the VEGF family. VEGF-B residues essential for binding to the antibody are contributed by both monomers of the cytokine. Our detailed analysis reveals that the neutralising effect of the antibody occurs by virtue of the steric hindrance of the receptor-binding interface. These findings suggest that functional complementarity between VEGF-B and 2H10 can be harnessed both in analysing the therapeutic potential of VEGF-B and as an antagonist of receptor activation.
血管内皮生长因子（VEGF）B通过与VEGF受体1结合来影响血管形成。为了研究VEGF - B在生理和病理血管生成中生物学特性的具体情况，研发了一种通过抑制VEGF - B与VEGF受体1结合发挥作用的中和性抗VEGF - B抗体（2H10）。在此，我们展示了该抗体的Fab片段（Fab - 2H10）与VEGF - B“高度有序”相互作用的结构特征。两分子的Fab - 2H10结合到位于VEGF - B同二聚体各极的对称结合位点，赋予该复合物独特的U形拓扑结构，这在VEGF家族中此前尚未观察到。细胞因子的两个单体都提供了与抗体结合所必需的VEGF - B残基。我们的详细分析表明，抗体的中和作用是通过受体结合界面的空间位阻实现的。这些发现表明，VEGF - B与2H10之间的功能互补性可用于分析VEGF - B的治疗潜力以及作为受体激活的拮抗剂。
