Homology modeling of tissue-type plasminogen activator K1 domain and studies on the interactions between kringles and lysine.
The 3-D structure of t-PA K1 domain was predicted by the method of homology modeling. The putative lysine-binding pockets of t-PA K1, UK K, PLG K1 and K4 were determined by superimposing their 3-D structures to that of t-PA K2 domain, of which the lysine-binding pockets had been revealed previously. After that the key residues of lysine-binding pockets of kringles were identified. The structural analyses showed that both the electrostatic potential and hydrophobic complementarity were well matched between lysine and the binding pockets of t-PA K2, PLG K1 and K4, but for t-PA K1 and UK K domains the complementarity did not match well in one or both respects. It is proposed that this is the reason that t-PA K1 and UK K domains do not bear the ability to bind lysine. With the respect of improving the affinity for fibrin, new types of mutants of t-PA K1 and UK K domains were designed, and structural changes caused by mutation were predicted by simulating the residue replacements. The mutant structural models demonstrated that the molecular design was reasonable.
Beijing Institute of Biotechnology, China.
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Wang
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Liu
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Xu
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Huang
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Huang
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D018082:Kringles; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D010446:Peptide Fragments; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D010959:Tissue Plasminogen Activator / Q000737:chemistry*
D010446:Peptide Fragments; D010959:Tissue Plasminogen Activator; D008239:Lysine