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- PDB-3pdf: Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C -

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Basic information

Entry
Database: PDB / ID: 3pdf
TitleDiscovery of Novel Cyanamide-Based Inhibitors of Cathepsin C
ComponentsDipeptidyl peptidase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Two domains / Cystein Protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


dipeptidyl-peptidase I / peptidase activator activity involved in apoptotic process / positive regulation of proteolysis involved in protein catabolic process / negative regulation of myelination / positive regulation of microglial cell activation / Cargo concentration in the ER / dipeptidyl-peptidase activity / COPII-mediated vesicle transport / chloride ion binding / COPII-coated ER to Golgi transport vesicle ...dipeptidyl-peptidase I / peptidase activator activity involved in apoptotic process / positive regulation of proteolysis involved in protein catabolic process / negative regulation of myelination / positive regulation of microglial cell activation / Cargo concentration in the ER / dipeptidyl-peptidase activity / COPII-mediated vesicle transport / chloride ion binding / COPII-coated ER to Golgi transport vesicle / phosphatase binding / cysteine-type peptidase activity / endoplasmic reticulum-Golgi intermediate compartment membrane / MHC class II antigen presentation / proteolysis involved in protein catabolic process / positive regulation of apoptotic signaling pathway / T cell mediated cytotoxicity / azurophil granule lumen / protein-folding chaperone binding / collagen-containing extracellular matrix / lysosome / immune response / endoplasmic reticulum lumen / cysteine-type endopeptidase activity / intracellular membrane-bounded organelle / serine-type endopeptidase activity / centrosome / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region / nucleoplasm / identical protein binding / membrane
Similarity search - Function
Cathepsin C, exclusion domain / Cathepsin C exclusion / Cathepsin C, exclusion domain superfamily / Cathepsin C / Cathepsin C exclusion domain / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : ...Cathepsin C, exclusion domain / Cathepsin C exclusion / Cathepsin C, exclusion domain superfamily / Cathepsin C / Cathepsin C exclusion domain / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : / Peptidase C1A, papain C-terminal / Papain family cysteine protease / Papain family cysteine protease / Cysteine proteinases / Cysteine peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cathepsin B; Chain A / Lipocalin / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Beta Barrel / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-LXV / Dipeptidyl peptidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 Å
AuthorsZhao, B. / Laine, D.
CitationJournal: Acs Med.Chem.Lett. / Year: 2011
Title: Discovery of novel cyanamide-based inhibitors of cathepsin C.
Authors: Laine, D. / Palovich, M. / McCleland, B. / Petitjean, E. / Delhom, I. / Xie, H. / Deng, J. / Lin, G. / Davis, R. / Jolit, A. / Nevins, N. / Zhao, B. / Villa, J. / Schneck, J. / McDevitt, P. ...Authors: Laine, D. / Palovich, M. / McCleland, B. / Petitjean, E. / Delhom, I. / Xie, H. / Deng, J. / Lin, G. / Davis, R. / Jolit, A. / Nevins, N. / Zhao, B. / Villa, J. / Schneck, J. / McDevitt, P. / Midgett, R. / Kmett, C. / Umbrecht, S. / Peck, B. / Davis, A.B. / Bettoun, D.
History
DepositionOct 22, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.name / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / 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_ref_seq_dif / 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.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _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_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jul 26, 2023Group: Database references / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / database_2
Item: _chem_comp.pdbx_synonyms / _citation.country ..._chem_comp.pdbx_synonyms / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dipeptidyl peptidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,1826
Polymers49,8551
Non-polymers1,3275
Water5,098283
1
A: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)204,73024
Polymers199,4204
Non-polymers5,31020
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
crystal symmetry operation3_655-x+1,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area16170 Å2
ΔGint-42 kcal/mol
Surface area51420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.084, 88.784, 114.554
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dipeptidyl peptidase 1 / Cathepsin C


Mass: 49855.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSC, CPPI / Cell (production host): CHO-Lec cell / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P53634, dipeptidyl-peptidase I

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Sugars , 2 types, 3 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: 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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Non-polymers , 3 types, 285 molecules

#3: Chemical ChemComp-LXV / 2,5-dibromo-N-{(3R,5S)-1-[(Z)-iminomethyl]-5-methylpyrrolidin-3-yl}benzenesulfonamide


Mass: 425.139 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H15Br2N3O2S
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 283 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.17 Å3/Da / Density % sol: 43.31 %

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Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 1 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 39791 / Observed criterion σ(F): 2 / Observed criterion σ(I): 2

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Processing

Software
NameClassification
REFMACrefinement
CNSrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.85→44.41 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.934 / SU B: 2.756 / SU ML: 0.084 / Cross valid method: THROUGHOUT / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21038 2086 5.9 %RANDOM
Rwork0.18901 ---
obs0.19031 33128 94.21 %-
all-3979 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 17.814 Å2
Baniso -1Baniso -2Baniso -3
1-1.57 Å20 Å20 Å2
2---0.48 Å20 Å2
3----1.09 Å2
Refinement stepCycle: LAST / Resolution: 1.85→44.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2763 0 77 283 3123
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0222932
X-RAY DIFFRACTIONr_bond_other_d0.0010.021916
X-RAY DIFFRACTIONr_angle_refined_deg1.0071.9543991
X-RAY DIFFRACTIONr_angle_other_deg0.7673.0054609
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5435348
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.55823.926135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.99815425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3971510
X-RAY DIFFRACTIONr_chiral_restr0.0560.2419
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023270
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02631
X-RAY DIFFRACTIONr_nbd_refined0.1840.2628
X-RAY DIFFRACTIONr_nbd_other0.1810.21983
X-RAY DIFFRACTIONr_nbtor_refined0.1860.21445
X-RAY DIFFRACTIONr_nbtor_other0.0840.21401
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1060.2235
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1410.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2110.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0850.221
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4121.51761
X-RAY DIFFRACTIONr_mcbond_other0.0561.5723
X-RAY DIFFRACTIONr_mcangle_it0.73122774
X-RAY DIFFRACTIONr_scbond_it0.83831364
X-RAY DIFFRACTIONr_scangle_it1.3244.51217
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.243 127 -
Rwork0.236 2218 -
obs--86.18 %

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