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

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Basic information

Entry
Database: PDB / ID: 1lya
TitleCRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN
Components(CATHEPSIN DCathepsin) x 2
KeywordsLYSOSOMAL ASPARTIC PROTEASE
Function / homology
Function and homology information


cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / lipoprotein catabolic process / insulin catabolic process / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / autophagosome assembly / Collagen degradation / Metabolism of Angiotensinogen to Angiotensins ...cathepsin D / aspartic-type peptidase activity / regulation of establishment of protein localization / lipoprotein catabolic process / insulin catabolic process / insulin receptor recycling / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / autophagosome assembly / Collagen degradation / 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 / lysosome / aspartic-type endopeptidase activity / 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
Biological speciesHomo 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: Derived calculations / Version format compliance
Revision 1.3Nov 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_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
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
C: CATHEPSIN D
D: CATHEPSIN D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8588
Polymers73,9184
Non-polymers1,9404
Water82946
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: CATHEPSIN D
B: CATHEPSIN D
hetero molecules

C: CATHEPSIN D
D: CATHEPSIN D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8588
Polymers73,9184
Non-polymers1,9404
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_664-y+1,x-y+1,z-1/31
Buried area17840 Å2
ΔGint-66 kcal/mol
Surface area26780 Å2
MethodPISA
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: CIS PROLINE - PRO A 24 / 2: CIS PROLINE - PRO A 95 / 3: CIS PROLINE - PRO B 177 / 4: CIS PROLINE - PRO B 314 / 5: CIS PROLINE - PRO B 317 / 6: CIS PROLINE - PRO C 2 / 7: CIS PROLINE - PRO C 24 / 8: CIS PROLINE - PRO C 95 / 9: CIS PROLINE - PRO D 177
10: PRO D 313 - PRO D 314 OMEGA = 36.80 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION
11: 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

#1: Protein CATHEPSIN D / Cathepsin


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 / Cathepsin


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
#3: 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
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.22 Å3/Da / Density % sol: 61.8 %
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
RefinementResolution: 2.5→10 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
RfactorNum. reflection
Rwork0.188 -
obs0.188 28077
Refinement stepCycle: LAST / Resolution: 2.5→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5186 0 128 46 5360
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_deg3.1
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 / Lowest resolution: 10 Å / Num. reflection obs: 28077 / Rfactor obs: 0.188
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_d3.1
X-RAY DIFFRACTIONx_dihedral_angle_d27.3
X-RAY DIFFRACTIONx_dihedral_angle_deg1.14

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