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- PDB-1lyb: CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPS... -

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Basic information

Entry
Database: PDB / ID: 1lyb
TitleCRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN
Components
  • (CATHEPSIN D) x 2
  • PEPSTATIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / LYSOSOMAL ASPARTIC PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / insulin catabolic process / lipoprotein catabolic process / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / Collagen degradation / autophagosome assembly / Metabolism of Angiotensinogen to Angiotensins ...cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / insulin catabolic process / lipoprotein catabolic process / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / Collagen degradation / autophagosome assembly / Metabolism of Angiotensinogen to Angiotensins / Insulin receptor recycling / MHC class II antigen presentation / lysosomal lumen / endosome lumen / specific granule lumen / antigen processing and presentation of exogenous peptide antigen via MHC class II / melanosome / tertiary granule lumen / peptidase activity / collagen-containing extracellular matrix / Estrogen-dependent gene expression / ficolin-1-rich granule lumen / aspartic-type endopeptidase activity / lysosome / endosome membrane / positive regulation of apoptotic process / membrane raft / lysosomal membrane / cysteine-type endopeptidase activity / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Cathepsin D / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Pepstatin / Cathepsin D
Similarity search - Component
Biological speciesStreptomyces argenteolus subsp. toyonakensis (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.5 Å
AuthorsBaldwin, E.T. / Bhat, T.N. / Gulnik, S. / Erickson, J.W.
Citation
Journal: Proc.Natl.Acad.Sci.USA / Year: 1993
Title: Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
Authors: 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.
#1: Journal: J.Mol.Biol. / Year: 1992
Title: Human Liver Cathepsin D. Purification, Crystallization and Preliminary X-Ray Diffraction Analysis of a Lysosomal Enzyme
Authors: Gulnik, S. / Baldwin, E.T. / Tarasova, N. / Erickson, J.
History
DepositionApr 22, 1993Processing site: BNL
Revision 1.0Jan 31, 1994Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Feb 27, 2013Group: Other
Revision 1.4Nov 29, 2017Group: Derived calculations / Other
Category: pdbx_database_status / struct_conf / struct_conf_type
Item: _pdbx_database_status.process_site
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 3.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Remark 700SHEET THERE ARE SEVERAL BIFURCATED SHEETS IN THIS STRUCTURE. THESE ARE REPRESENTED BY TWO SHEETS ...SHEET THERE ARE SEVERAL BIFURCATED SHEETS IN THIS STRUCTURE. THESE ARE REPRESENTED BY TWO SHEETS WHICH HAVE ONE OR MORE IDENTICAL STRANDS. SHEETS *1A1* AND *1B1* AND SHEETS *1A2* AND *1B2* REPRESENT ONE BIFURCATED SHEET IN EACH MOLECULE. SHEETS *2A1* AND *2B1* AND *2A2* AND *2B2* REPRESENT ONE BIFURCATED SHEET IN EACH MOLECULE.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CATHEPSIN D
B: CATHEPSIN D
I: PEPSTATIN
C: CATHEPSIN D
D: CATHEPSIN D
J: PEPSTATIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,23010
Polymers75,2906
Non-polymers1,9404
Water79344
1
A: CATHEPSIN D
B: CATHEPSIN D
I: PEPSTATIN
hetero molecules

C: CATHEPSIN D
D: CATHEPSIN D
J: PEPSTATIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,23010
Polymers75,2906
Non-polymers1,9404
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_664-y+1,x-y+1,z-1/31
Buried area20830 Å2
ΔGint-94 kcal/mol
Surface area26050 Å2
MethodPISA
2
A: CATHEPSIN D
B: CATHEPSIN D
I: PEPSTATIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6155
Polymers37,6453
Non-polymers9702
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
3
C: CATHEPSIN D
D: CATHEPSIN D
J: PEPSTATIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6155
Polymers37,6453
Non-polymers9702
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)125.900, 125.900, 104.100
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65
Atom site foot note1: GLY A 1 - PRO A 2 OMEGA =326.44 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION
2: CIS PROLINE - PRO A 24 / 3: CIS PROLINE - PRO A 95 / 4: CIS PROLINE - PRO B 177 / 5: CIS PROLINE - PRO B 314 / 6: CIS PROLINE - PRO B 317 / 7: CIS PROLINE - PRO C 2 / 8: CIS PROLINE - PRO C 24 / 9: CIS PROLINE - PRO C 95 / 10: CIS PROLINE - PRO D 177
11: PRO D 312 - PRO D 313 OMEGA =149.72 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION
12: CIS PROLINE - PRO D 314 / 13: CIS PROLINE - PRO D 317
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (0.7353, 0.6747, -0.06415), (0.6088, -0.6992, -0.3748), (-0.2978, 0.2366, -0.9249)
Vector: -9.5784, 129.91299, 10.6518)
DetailsTHE TRANSFORMATION PRESENTED ON *MTRIX* RECORDS BELOW WILL YIELD APPROXIMATE COORDINATES FOR CHAINS *A* AND *B* WHEN APPLIED TO CHAINS *C* AND *D*, RESPECTIVELY.

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein CATHEPSIN D


Mass: 10688.941 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: LIVER / Tissue: LIVER / References: UniProt: P07339, cathepsin D
#2: Protein CATHEPSIN D


Mass: 26270.207 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: LIVER / Tissue: LIVER / References: UniProt: P07339, cathepsin D

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Protein/peptide / Non-polymers , 2 types, 46 molecules IJ

#3: Protein/peptide PEPSTATIN


Type: Oligopeptide / Class: Enzyme inhibitor / Mass: 685.891 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Streptomyces argenteolus subsp. toyonakensis (bacteria)
References: Pepstatin
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 4 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...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


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.16 Å3/Da / Density % sol: 61.1 %
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 5.1 / Method: vapor diffusion, hanging drop
Details: taken from Gulnik, S. et al (1992). J. Mol. Biol., 227, 265-270.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
120 mg/mlenzyme1drop
250 mMsodium acetate1reservoir
365 %satammonium sulfate1reservoir

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Data collection

RadiationScattering type: x-ray
Radiation wavelengthRelative weight: 1

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Processing

Software
NameVersionClassification
X-PLOR3model building
X-PLOR3refinement
X-PLOR3phasing
RefinementRfactor Rwork: 0.179 / Rfactor obs: 0.179 / Highest resolution: 2.5 Å
Details: THERE ARE TWO N-LINKED OLIGOSACCHARIDES ATTACHED AT RESIDUES ASN 70 AND ASN 199 OF EACH MOLECULE. FOUR SUGARS WERE INCLUDED FOR REFINEMENT AT ASN 70 AND A SINGLE N-LINKED NAG AT ASN 199. THE ...Details: THERE ARE TWO N-LINKED OLIGOSACCHARIDES ATTACHED AT RESIDUES ASN 70 AND ASN 199 OF EACH MOLECULE. FOUR SUGARS WERE INCLUDED FOR REFINEMENT AT ASN 70 AND A SINGLE N-LINKED NAG AT ASN 199. THE SUGARS ARE LINKED AS FOLLOWS: ASN A 70 -- NAG A 1 -- NAG A 2 -- MAN A 3 -- MAN A 8 ASN B 199 -- NAG B 1 ASN C 70 -- NAG C 1 -- NAG C 2 -- MAN C 3 -- MAN C 8 ASN D 199 -- NAG D 1
Refinement stepCycle: LAST / Highest resolution: 2.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5282 0 128 44 5454
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.012
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg3.2
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
Software
*PLUS
Name: X-PLOR / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.5 Å / Rfactor obs: 0.179
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_d3.2
X-RAY DIFFRACTIONx_dihedral_angle_d26.6
X-RAY DIFFRACTIONx_dihedral_angle_deg1.14

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