Abstract
The crystal structure of the inhibitor NS-134 in complex with bovine cathepsin B reveals that functional groups attached to both sides of the epoxysuccinyl reactive group bind to the part of active-site cleft as predicted. The -Leu-Pro-OH side binds to the primed binding sites interacting with the His110 and His111 residues with its C-terminal carboxy group, whereas the -Leu-Gly-Meu (-Leu-Gly-Gly-OMe) part (Meu, methoxycarbonylmethyl) binds along the non-primed binding sites. Comparison with the propeptide structures of cathepsins revealed that the binding of the latter part is least similar to the procathepsin B structure; this result, together with the two-residue shift in positioning of the Leu-Gly-Gly part, suggests that the propeptide structures of the cognate enzymes may not be the best starting point for the design of reverse binding inhibitors.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Animals
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Binding Sites
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Cathepsin B / antagonists & inhibitors
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Cathepsin B / chemistry*
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Cathepsin B / isolation & purification
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Cattle
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Crystallography, X-Ray / methods*
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Cysteine Proteinase Inhibitors / chemistry
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Dipeptides / chemistry
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Epoxy Compounds / chemistry
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Kidney / enzymology
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Leucine / analogs & derivatives*
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Leucine / chemistry
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Molecular Conformation
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Molecular Structure
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Oligopeptides / chemical synthesis
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Oligopeptides / chemistry*
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Protein Binding
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Protein Conformation
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Protein Structure, Quaternary
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Pyridines / chemistry
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
Substances
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1-(2-((3-(1-(((methoxycarbonylmethyl-carbamoyl)-methyl)-carbamoyl)-3-methyl-butylcarbamoyl)-oxiranecarbonyl)-amino)-4-methyl-pentanoyl)-pyrrolidine-2-carboxylic acid
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CLIK 148
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Cysteine Proteinase Inhibitors
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Dipeptides
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Epoxy Compounds
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Oligopeptides
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Pyridines
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Pyrroles
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N-(3-ethoxycarbonyloxirane-2-carbonyl)-isoleucyl-proline
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N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline
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Cathepsin B
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Leucine
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E 64