1SP4

Crystal structure of NS-134 in complex with bovine cathepsin B: a two headed epoxysuccinyl inhibitor extends along the whole active site cleft

Summary for 1SP4

• Entry DOI: 10.2210/pdb1sp4/pdb
• Related PRD ID: PRD_000444
• Descriptor: Cathepsin B, methyl N-[(2S)-4-{[(1S)-1-{[(2S)-2-carboxypyrrolidin-1-yl]carbonyl}-3-methylbutyl]amino}-2-hydroxy-4-oxobutanoyl]-L-leucylglycylglycinate, ... (4 entities in total)
• Functional Keywords: cathepsin b, epoxysuccinyl-based inhibitors, inhibitor design, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (cattle); More
• Cellular location: Lysosome : P07688 P07688
• Total number of polymer chains: 2
• Total formula weight: 28118.24

Authors

Stern, I.,Schaschke, N.,Moroder, L.,Turk, D. (deposition date: 2004-03-16, release date: 2004-05-04, Last modification date: 2024-10-09)

Primary citation

Stern, I.,Schaschke, N.,Moroder, L.,Turk, D.
Crystal structure of NS-134 in complex with bovine cathepsin B: a two-headed epoxysuccinyl inhibitor extends along the entire active-site cleft.
Biochem.J., 381:511-517, 2004

PubMed 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.

PubMed: 15084146
DOI: 10.1042/BJ20040237

Experimental method

X-RAY DIFFRACTION (2.2 Å)