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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
14
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pubmed:dateCreated |
1993-8-30
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/8393577-1331081,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/8393577-875032
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
90
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6796-800
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:8393577-Amino Acid Sequence,
pubmed-meshheading:8393577-Aspartic Acid Endopeptidases,
pubmed-meshheading:8393577-Biological Transport,
pubmed-meshheading:8393577-Cathepsin D,
pubmed-meshheading:8393577-Drug Design,
pubmed-meshheading:8393577-Glycosylation,
pubmed-meshheading:8393577-Humans,
pubmed-meshheading:8393577-Lysosomes,
pubmed-meshheading:8393577-Models, Molecular,
pubmed-meshheading:8393577-Molecular Sequence Data,
pubmed-meshheading:8393577-Pepstatins,
pubmed-meshheading:8393577-Phosphotransferases,
pubmed-meshheading:8393577-Protein Conformation,
pubmed-meshheading:8393577-Renin,
pubmed-meshheading:8393577-X-Ray Diffraction
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pubmed:year |
1993
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pubmed:articleTitle |
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
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pubmed:affiliation |
Structural Biochemistry Program, Program Resources Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.
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