1LYB

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Work: 0.179 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


This is version 3.0 of the entry. See complete history


Literature

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

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.

(1993) Proc Natl Acad Sci U S A 90: 6796-6800

  • DOI: https://doi.org/10.1073/pnas.90.14.6796
  • Primary Citation of Related Structures:  
    1LYA, 1LYB

  • 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.


  • Organizational Affiliation

    Structural Biochemistry Program, Program Resources Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CATHEPSIN DA,
D [auth C]
97Homo sapiensMutation(s): 0 
EC: 3.4.23.5
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P07339 (Homo sapiens)
Explore P07339 
Go to UniProtKB:  P07339
PHAROS:  P07339
GTEx:  ENSG00000117984 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07339
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CATHEPSIN DB,
E [auth D]
241Homo sapiensMutation(s): 0 
EC: 3.4.23.5
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P07339 (Homo sapiens)
Explore P07339 
Go to UniProtKB:  P07339
PHAROS:  P07339
GTEx:  ENSG00000117984 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07339
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
PEPSTATINC [auth I],
F [auth J]
6Streptomyces argenteolus subsp. toyonakensisMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
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-glucopyranoseG [auth E],
H [auth F]
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22573RC
GlyCosmos:  G22573RC
GlyGen:  G22573RC
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
I [auth B],
J [auth D]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Entity ID: 3
IDChains NameType/Class2D Diagram3D Interactions
PRD_000557
Query on PRD_000557
C [auth I],
F [auth J]
PepstatinOligopeptide / Enzyme inhibitor
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Work: 0.179 
  • R-Value Observed: 0.179 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.9α = 90
b = 125.9β = 90
c = 104.1γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1994-01-31
    Type: Initial release
  • Version 1.1: 2008-03-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2013-02-27
    Changes: Other
  • Version 1.4: 2017-11-29
    Changes: Derived calculations, Other
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 3.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Structure summary