Structural basis of inhibition of cysteine proteases by E-64 and its derivatives.
This paper focuses on the inhibitory mechanism of E-64 and its derivatives (epoxysuccinyl-based inhibitors) with some cysteine proteases, based on the binding modes observed in the x-ray crystal structures of their enzyme-inhibitor complexes. E-64 is a potent irreversible inhibitor against general cysteine proteases, and its binding modes with papain, actinidin, cathepsin L, and cathepsin K have been reviewed at the atomic level. E-64 interacts with the Sn subsites of cysteine proteases. Although the Sn-Pn (n = 1-3) interactions of the inhibitor with the main chains of the active site residues are similar in respective complexes, the significant difference is observed in the side-chain interactions of S2-P2 and S3-P3 pairs because of different residues constituting the respective subsites. E-64-c and CA074 are representative derivatives developed from E-64 as a clinical usable and a cathepsin B-specific inhibitors, respectively. In contrast with similar binding/inhibitory modes of E-64-c and E-64 for cysteine proteases, the inhibitory mechanism of cathepsin B-specific CA074 results from the binding to the Sn' subsite.
Matsumoto
K
K
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Mizoue
K
K
Kitamura
K
K
Tse
W C
WC
Huber
C P
CP
Ishida
T
T
D001665:Binding Sites; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004852:Epoxy Compounds; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D055672:Static Electricity; D013329:Structure-Activity Relationship; D019802:Succinic Acid
D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D019802:Succinic Acid; D003546:Cysteine Endopeptidases; D007930:Leucine; C024974:E 64