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The crystallographic structure of the plasminogen kringle 4-epsilon-aminocaproic
acid (ACA) complex (K4-ACA) has been solved by molecular replacement
rotation-translation methods utilizing the refined apo-K4 structure as a search
model (Mulichak et al., 1991), and it has been refined to an R value of 0.148 at
2.25-A resolution. The K4-ACA structure consists of two interkringle residues,
the kringle along with the ACA ligand, and 106 water molecules. The
lysine-binding site has been confirmed to be a relatively open and shallow
depression, lined by aromatic rings of Trp62, Phe64, and Trp72, which provide a
highly nonpolar environment between doubly charged anionic and cationic centers
formed by Asp55/Asp57 and Lys35/Arg71. A zwitterionic ACA ligand molecule is
held by hydrogen-bonded ion pair interactions and van der Waals contacts between
the charged centers. The lysine-binding site of apo-K4 and K4-ACA have been
compared: the rms differences in main-chain and side-chain positions are 0.25
and 0.69 A, respectively, both practically within error of the determinations.
The largest deviations in the binding site are due to different crystal packing
interactions. Thus, the lysine-binding site appears to be preformed, and lysine
binding does not require conformational changes of the host. The results of NMR
studies of lysine binding with K4 are correlated with the structure of K4-ACA
and agree well.
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