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Title
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Lysine/fibrin binding sites of kringles modeled after the structure of kringle 1 of prothrombin.
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Authors
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A.Tulinsky,
C.H.Park,
B.Mao,
M.Llinás.
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Ref.
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Proteins, 1988,
3,
85-96.
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PubMed id
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Abstract
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The Lys binding site of kringle 1 and 4 (K1 and K4) of plasminogen (PG) has been
modeled on the basis of the three-dimensional structure of kringle 1 of
prothrombin and 300- and 600-MHZ proton nuclear magnetic resonance observations.
These structures were then compared to the corresponding regions of modeled
kringle 1 and 2 of tissue plasminogen activator (PA). The coordinates of the
modeled structures have been refined by energy minimization in the presence and
absence of epsilon-aminocaproic acid ligand in order basically to remove
unacceptable van der Waals contacts. The binding site is characterized by an
apparent dipolar surface, the polar parts of which are separated by a
hydrophobic region of highly conserved aromatic residues. Zwitterionic ligands
such as Lys and epsilon-aminocaproic acid form ion pair interactions with Asp55
and Asp57 located on the dipolar surface; the latter are also conserved in all
the Lys binding kringles. The cationic center of the dipolar surface is Arg71,
in the case of PGK4, and is composed of Arg34 and Arg71 in PGK1. The doubly
charged anionic/cationic interaction centers of the latter might account for the
larger binding constants of PGK1 for like-ligands but the modeling suggests that
PGK4 might be kinetically faster in binding bulkier ligands. The binding site
region of PAK2, which also binds Lys, resembles those of PGK1 and PGK4. Since
PAK2 lacks both cationic center Arg residues, ligand carboxylate binding appears
to be accomplished though an imidazolium ion of His64, which is located just
below the outer surface of the kringle.
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