1hpj: Difference between revisions
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==Overview== | ==Overview== | ||
The solution structure of the human plasminogen kringle 1 domain complexed, to the antifibrinolytic drug 6-aminohexanoic acid (epsilon Ahx) was, obtained on the basis of 1H-NMR spectroscopic data and dynamical simulated, annealing calculations. Two sets of structures were derived starting from, (a) random coil conformations and (b) the (mutated) crystallographic, structure of the homologous prothrombin kringle 1. The two sets display, essentially the same backbone folding (pairwise root-mean-square, deviation, 0.15 nm) indicating that, regardless of the initial structure, the data is sufficient to locate a conformation corresponding to an, essentially unique energy minimum. The conformations of residues connected, to prolines were localized to energetically preferred regions of the, Ramachandran map. The Pro30 peptide bond is proposed to be cis. The, ligand-binding site of the kringle 1 is a shallow cavity composed of, Pro33, Phe36, Trp62, Tyr64, Tyr72 and Tyr74. Doubly charged anionic and, cationic centers configured by the side chains of Asp55 and Asp57, and, Arg34 and Arg71, respectively, contribute to anchoring the zwitterionic, epsilon Ahx molecule at the binding site. The ligand exhibits closer, contacts with the kringle anionic centers (approximately 0.35 nm average, O...H distance between the Asp55/Asp57 carboxylate and ligand amino, groups) than with the cationic ones (approximately 0.52 nm closest O...H, distances between the ligand carboxylate and the Arg34/Arg71 guanidino, groups). The epsilon Ahx hydrocarbon chain rests flanked by Pro33, Tyr64, Tyr72 and Tyr74 on one side and Phe36 on the other. Dipolar (Overhauser), connectivities indicate that the ligand aliphatic moiety establishes close, contacts with the Phe36 and Trp62 aromatic rings. The computed structure, suggests that the epsilon Ahx molecule adopts a kinked conformation when, complexed to kringle 1, effectively shortening its dipole length to, approximately 0.65 nm. | The solution structure of the human plasminogen kringle 1 domain complexed, to the antifibrinolytic drug 6-aminohexanoic acid (epsilon Ahx) was, obtained on the basis of 1H-NMR spectroscopic data and dynamical simulated, annealing calculations. Two sets of structures were derived starting from, (a) random coil conformations and (b) the (mutated) crystallographic, structure of the homologous prothrombin kringle 1. The two sets display, essentially the same backbone folding (pairwise root-mean-square, deviation, 0.15 nm) indicating that, regardless of the initial structure, the data is sufficient to locate a conformation corresponding to an, essentially unique energy minimum. The conformations of residues connected, to prolines were localized to energetically preferred regions of the, Ramachandran map. The Pro30 peptide bond is proposed to be cis. The, ligand-binding site of the kringle 1 is a shallow cavity composed of, Pro33, Phe36, Trp62, Tyr64, Tyr72 and Tyr74. Doubly charged anionic and, cationic centers configured by the side chains of Asp55 and Asp57, and, Arg34 and Arg71, respectively, contribute to anchoring the zwitterionic, epsilon Ahx molecule at the binding site. The ligand exhibits closer, contacts with the kringle anionic centers (approximately 0.35 nm average, O...H distance between the Asp55/Asp57 carboxylate and ligand amino, groups) than with the cationic ones (approximately 0.52 nm closest O...H, distances between the ligand carboxylate and the Arg34/Arg71 guanidino, groups). The epsilon Ahx hydrocarbon chain rests flanked by Pro33, Tyr64, Tyr72 and Tyr74 on one side and Phe36 on the other. Dipolar (Overhauser), connectivities indicate that the ligand aliphatic moiety establishes close, contacts with the Phe36 and Trp62 aromatic rings. The computed structure, suggests that the epsilon Ahx molecule adopts a kinked conformation when, complexed to kringle 1, effectively shortening its dipole length to, approximately 0.65 nm. | ||
==Disease== | |||
Known diseases associated with this structure: Conjunctivitis, ligneous OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=173350 173350]], Plasminogen Tochigi disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=173350 173350]], Plasminogen deficiency, types I and II OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=173350 173350]], Thrombophilia, dysplasminogenemic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=173350 173350]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:21:07 2007'' | ||