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

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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Hosur, M. V. Gulnik, S. Collins, J. Baldwin, E. T. Sowder, R. C. Silva, A. M. Bhat, T. N. Cachau, R. E. Erickson, J. W.
Description	Author Affiliation: Baldwin ET ( Structural Biochemistry Program, Program Resources Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.);
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.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	14
Volume Number	90
Language	English
Publisher	National Academy of Sciences
Publisher Date	1993-08-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cathepsin D Antagonists & Inhibitors Chemistry Pepstatins Amino Acid Sequence Aspartic Acid Endopeptidases Biological Transport Drug Design Glycosylation Lysosomes Models, Molecular Molecular Sequence Data Phosphotransferases Protein Conformation Renin X-Ray Diffraction Comparative Study Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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