1KAT

Solution Structure of a Phage-Derived Peptide Antagonist in Complex with Vascular Endothelial Growth Factor

1KAT の概要

• エントリーDOI: 10.2210/pdb1kat/pdb
• NMR情報: BMRB: 5185
• 分子名称: Vascular Endothelial Growth Factor, Phage-Derived Peptide Antagonist (2 entities in total)
• 機能のキーワード: protein-peptide complex, homodimer, cystine knot, cell cycle, hormone-growth factor complex, hormone/growth factor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P15692
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 27992.03

構造登録者

Pan, B.,Li, B.,Russell, S.J.,Tom, J.Y.K.,Cochran, A.G.,Fairbrother, W.J. (登録日: 2001-11-02, 公開日: 2002-11-02, 最終更新日: 2024-11-20)

主引用文献

Pan, B.,Li, B.,Russell, S.J.,Tom, J.Y.K.,Cochran, A.G.,Fairbrother, W.J.
Solution Structure of a Phage-derived Peptide Antagonist in Complex with Vascular Endothelial Growth Factor
J.Mol.Biol., 316:769-787, 2002

PubMed Abstract: 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.

PubMed: 11866530
DOI: 10.1006/jmbi.2001.5370

実験手法

SOLUTION NMR