Dataset Information


Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.

ABSTRACT: Cathepsin D (EC is a lysosomal protease suspected to play important roles in protein catabolism, antigen processing, degenerative diseases, and breast cancer progression. Determination of the crystal structures of cathepsin D and a complex with pepstatin at 2.5 A resolution provides insights into inhibitor binding and lysosomal targeting for this two-chain, N-glycosylated aspartic protease. Comparison with the structures of a complex of pepstatin bound to rhizopuspepsin and with a human renin-inhibitor complex revealed differences in subsite structures and inhibitor-enzyme interactions that are consistent with affinity differences and structure-activity relationships and suggest strategies for fine-tuning the specificity of cathepsin D inhibitors. Mutagenesis studies have identified a phosphotransferase recognition region that is required for oligosaccharide phosphorylation but is 32 A distant from the N-domain glycosylation site at Asn-70. Electron density for the crystal structure of cathepsin D indicated the presence of an N-linked oligosaccharide that extends from Asn-70 toward Lys-203, which is a key component of the phosphotransferase recognition region, and thus provides a structural explanation for how the phosphotransferase can recognize apparently distant sites on the protein surface.


PROVIDER: S-EPMC47019 | BioStudies | 1993-01-01T00:00:00Z


REPOSITORIES: biostudies

Similar Datasets

1988-01-01 | S-EPMC1135455 | BioStudies
1989-01-01 | S-EPMC1133469 | BioStudies
1984-01-01 | S-EPMC1144311 | BioStudies
1980-01-01 | S-EPMC1161587 | BioStudies
1976-01-01 | S-EPMC1172808 | BioStudies
2010-01-01 | S-EPMC3055766 | BioStudies
1980-01-01 | S-EPMC1162283 | BioStudies
1000-01-01 | S-EPMC2691902 | BioStudies
2008-01-01 | S-EPMC2292629 | BioStudies
1981-01-01 | S-EPMC1163417 | BioStudies