1LYB

CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN

Summary for 1LYB

• Entry DOI: 10.2210/pdb1lyb/pdb
• Related PRD ID: PRD_000557
• Descriptor: CATHEPSIN D, PEPSTATIN, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: lysosomal aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Streptomyces argenteolus subsp. toyonakensis; More
• Total number of polymer chains: 6
• Total formula weight: 77229.86

Authors

Baldwin, E.T.,Bhat, T.N.,Gulnik, S.,Erickson, J.W. (deposition date: 1993-04-22, release date: 1994-01-31, Last modification date: 2024-10-23)

Primary citation

Baldwin, E.T.,Bhat, T.N.,Gulnik, S.,Hosur, M.V.,Sowder 2nd., R.C.,Cachau, R.E.,Collins, J.,Silva, A.M.,Erickson, J.W.
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
Proc.Natl.Acad.Sci.USA, 90:6796-6800, 1993

PubMed Abstract: Cathepsin D (EC 3.4.23.5) 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.

PubMed: 8393577
DOI: 10.1073/pnas.90.14.6796

Experimental method

X-RAY DIFFRACTION (2.5 Å)