The X-ray crystallographic structures of the angiogenesis inhibitor angiostatin bound to a peptide from the group A streptococcal surface protein PAM and the metal-bound conantokins con-G and con-T[K7gamma]. Sara Elizabeth Cnuddle

ISBN: 9780549618089

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174 pages


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The X-ray crystallographic structures of the angiogenesis inhibitor angiostatin bound to a peptide from the group A streptococcal surface protein PAM and the metal-bound conantokins con-G and con-T[K7gamma].  by  Sara Elizabeth Cnuddle

The X-ray crystallographic structures of the angiogenesis inhibitor angiostatin bound to a peptide from the group A streptococcal surface protein PAM and the metal-bound conantokins con-G and con-T[K7gamma]. by Sara Elizabeth Cnuddle
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Angiostatin is a fragment of plasminogen encompassing the first three kringle domains. Plasminogen is the zymogen of plasmin that is known to bind C-terminal lysine residues in fibrin through the kringle domain lysine binding site. The firstMoreAngiostatin is a fragment of plasminogen encompassing the first three kringle domains.

Plasminogen is the zymogen of plasmin that is known to bind C-terminal lysine residues in fibrin through the kringle domain lysine binding site. The first structure of a multi-kringle containing compound bound to a ligand was not done until the structure of the angiostatin/VEK-30 complex was determined and refined to 2.3 A resolution that of which is described herein. It provides a model of the interaction between plasminogen and streptococcal-derived pathogenic proteins during infection. VEK-30 contains a through-space isostere for C-terminal lysine, wherein Arg and Glu side chains, separated by one helical turn, bind within the bipolar angiostatin kringle 2 (K2)-domain lysine-binding site.

VEK-30 also makes several contacts with K2 residues that exist outside of the canonical LBS and are not conserved among the other plasminogen kringles, thus providing a molecular basis for the selectivity of VEK-30 for K2. The structure also shows that plasminogen kringle domains undergo significant structural rearrangement relative to one another, and reveals dimerization between two molecules of angiostatin/VEK-30 related by crystallographic symmetry.

This dimerization, which only exists in the crystal structure, is consistent with the parallel coiled-coil full-length PAM dimer expected from sequence similarities and homology modeling.-The challenge of generating a small, unstructured peptide capable of metal ion-triggered helix formation and self-association has been satisfied in nature with the peptide conantokin-G (con-G). Con-G antagonizes the N-methyl-D-aspartate (NMDA) receptors. Con-G is 17 residues and contains five gamma-carboxyglumates (Gla).

A variety of metals can promote a conformational change from random coil to a helix, but only Ca2+ allows for the formation of a dimeric con-G complex. From these data, we proposed a model for the complex in which antiparallel con-G strands are stabilized solely through Ca 2+-bridging of Gla headgroups within the helix-helix interface. This model represents a heretofore unknown motif which we define as the metallo-zipper. A second member from the conantokin family, conantokin-T (con-T), shares some sequence identity to con-G. However, several primary and secondary structural differences exist between con-G and con-T, specificially at position 7, which is occupied by Lys in con-T and Gla in con-G.

While con-T does not undergo Ca2+-induced self-assembly, replacing the Lys with a Gla (con-T[K7gamma]) allows it to form an antiparallel helix dimer in the presence of Ca 2+. However the dimer interface is substantially different from con-G.-We were able to further understand metal-dependant dimerization and helix stabilization by determining the structure of the peptide bound to different metals, such as Cd2+ and Mg2+.

X-ray structures have been determined of Ca2+-complexed con-G and con-T[K7gamma] at high resolution (1.2 A for con-G and 1.6 A for con-T[K7gamma]) as well as Mg2+/Cd2+-complexed con-T[K7gamma] at 1.2 A.



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