The X-ray Crystallographic Structure of the Angiogenesis Inhibitor Angiostatin

• Published in: Journal of molecular biology Vol. 318; no. 4; pp. 1009 - 1017
• Main Authors: Abad, Marta C., Arni, R.K., Grella, Davida K., Castellino, Francis J., Tulinsky, Alexander, Geiger, James H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 10.05.2002
• Subjects: Amino Acid Sequence; angiogenesis; Angiogenesis Inhibitors - chemistry; Angiostatins; coagulation; crystal structure; Crystallization; Crystallography, X-Ray; Humans; kringle domains; Kringles; Models, Molecular; Molecular Sequence Data; Mutation; Peptide Fragments - chemistry; Pichia; plasminogen; Plasminogen - chemistry; Protein Conformation; Sequence Homology, Amino Acid; LBS, lysine-binding site; NK1, N-terminal and kringle 1 domains of human hepatocyte growth factor; angiogenesis; K, kringle domains; EPS, electrostatic potential surface; VEGF, vascular endothelial growth factor; rmsd, root-mean-square deviation; coagulation; PAM, group A streptococcal surface protein; plasminogen; kringle domains; EACA, ε-aminocaproic acid; bFGF, basic fibroblast growth factor; crystal structure; VEK-30, 30 residue peptide encompassing 85–114 of the PAM sequence
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/S0022-2836(02)00211-5

Angiogenesis inhibitors have gained much public attention recently as anti-cancer agents and several are currently in clinical trials, including angiostatin (Phase I, Thomas Jefferson University Hospital, Philadelphia, PA). We report here the bowl-shaped structure of angiostatin kringles 1–3, the first multi-kringle structure to be determined. All three kringle lysine-binding sites contain a bound bicine molecule of crystallization while the former of kringle 2 and kringle 3 are cofacial. Moreover, the separation of the kringle 2 and kringle 3 lysiner binding sites is sufficient to accommodate the α-helix of the 30 residue peptide VEK-30 found in the kringle 2/VEK-30 complex. Together the three kringles produce a central cavity suggestive of a unique domain where they may function in concert.