Solution structure of a phage-derived peptide antagonist in complex with vascular endothelial growth factor.
Solution structure of a phage-derived peptide antagonist in complex with vascular endothelial growth factor.
复制标题
噬菌体衍生肽拮抗剂与血管内皮生长因子复合物的溶液结构。
DOI：
10.1006/jmbi.2001.5370
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发表时间：
2002
影响因子：
5.6
通讯作者：
W. Fairbrother
中科院分区：
文献类型：
--
作者：
B. Pan;Bing Li;S. Russell;J. Tom;A. Cochran;W. Fairbrother
血管内皮生长因子（VEGF）是一种有效的内皮细胞特异性血管生成和血管发生介质。VEGF在病理上参与癌症、增殖性视网膜病变和类风湿关节炎，因此是一个重要的治疗靶点。三种抑制VEGF二聚体与其受体KDR和Flt-1结合的二硫约束肽，先前通过噬菌体展示方法被鉴定出来。研究人员对这些肽拮抗剂中最有效的一类代表肽v107 （GGNECDAIRMWEWECFERL）进行了核磁共振研究，以表征其与VEGF的相互作用。v107在溶液中没有明确的自由结构，但与VEGF结合可诱导肽折叠。使用含有（13）C/(15) n标记的蛋白质加上多余的未标记肽或（13）C/(15) n标记的肽加上多余的未标记蛋白质的样品获得的NMR数据，通过3940（每个VEGF单体1970）核间距和476（每个VEGF单体238）二面角约束来确定VEGF受体结合域-v107复合物的溶液结构。残留的偶极偶联约束补充了复合物的结构确定，并被发现显著提高了复合物中VEGF的整体精度以及与VEGF可用晶体结构的一致性。计算得到的结构系综精度高，与实验约束条件吻合良好。V107具有旋螺旋构象，疏水残基分布在肽的一面，极性或带电残基分布在另一面。两个v107肽与VEGF二聚体之间的接触主要是通过疏水侧链相互作用介导的。VEGF上的v107结合位点与KDR的结合位点部分重叠，与Flt-1的结构域2相似。VEGF-v107复合物的结构为如何与VEGF结合提供了新的见解，这可能对小分子拮抗剂的设计有用。
Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific mediator of angiogenesis and vasculogenesis. VEGF is involved pathologically in cancer, proliferative retinopathy and rheumatoid arthritis, and as such represents an important therapeutic target. Three classes of disulfide-constrained peptides that antagonize binding of the VEGF dimer to its receptors, KDR and Flt-1, were identified previously using phage display methods. NMR studies of a representative peptide from the most potent class of these peptide antagonists, v107 (GGNECDAIRMWEWECFERL), were undertaken to characterize its interactions with VEGF. v107 has no defined structure free in solution, but binding to VEGF induces folding of the peptide. The solution structure of the VEGF receptor-binding domain-v107 complex was determined using 3940 (1970 per VEGF monomer) internuclear distance and 476 (238 per VEGF monomer) dihedral angle restraints derived from NMR data obtained using samples containing either (13)C/(15)N-labeled protein plus excess unlabeled peptide or (13)C/(15)N-labeled peptide plus excess unlabeled protein. Residual dipolar coupling restraints supplemented the structure determination of the complex and were found to increase significantly both the global precision of VEGF in the complex and the agreement with available crystal structures of VEGF. The calculated ensemble of structures is of high precision and is in excellent agreement with the experimental restraints. v107 has a turn-helix conformation with hydrophobic residues partitioned to one face of the peptide and polar or charged residues at the other face. Contacts between two v107 peptides and the VEGF dimer are mediated by primarily hydrophobic side-chain interactions. The v107-binding site on VEGF overlaps partially with the binding site of KDR and is similar to that for domain 2 of Flt-1. The structure of the VEGF-v107 complex provides new insight into how binding to VEGF can be achieved that may be useful for the design of small molecule antagonists.
影响因子：
56.9
作者：
DEVRIES, C;ESCOBEDO, JA;WILLIAMS, LT
通讯作者：
WILLIAMS, LT
影响因子：
56.9
作者：
JAMES, GL;GOLDSTEIN, JL;MARSTERS, JC
通讯作者：
MARSTERS, JC