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- PDB-6ic6: Human cathepsin-C in complex with cyclopropyl peptidyl nitrile in... -

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Basic information

Entry
Database: PDB / ID: 6ic6
TitleHuman cathepsin-C in complex with cyclopropyl peptidyl nitrile inhibitor 1
Components(Dipeptidyl peptidase ...) x 3
KeywordsHYDROLASE / cathepsin-C / cysteine protease / structure-based drug design / arthritis
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 / positive regulation of apoptotic signaling pathway / MHC class II antigen presentation / endoplasmic reticulum-Golgi intermediate compartment membrane / proteolysis involved in protein catabolic process / response to organic substance / 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 / serine-type endopeptidase activity / intracellular membrane-bounded organelle / centrosome / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region / nucleoplasm / membrane / identical protein binding
Similarity search - Function
Cathepsin C, exclusion domain / Cysteine proteinases. Chain C / 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 ...Cathepsin C, exclusion domain / Cysteine proteinases. Chain C / 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 / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / Alpha-Beta Complex / Beta Barrel / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-H9B / Dipeptidyl peptidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.898 Å
AuthorsHakansson, M. / Logan, D.T. / Korkmaz, B. / Lesner, A. / Wysocka, M. / Gieldon, A. / Gauthier, F. / Jenne, D. / Lauritzen, C. / Pedersen, J.
Funding support Poland, 1items
OrganizationGrant numberCountry
Polish National Science Centre2014/15/B/ST5/05311 Poland
CitationJournal: Biochem. Pharmacol. / Year: 2019
Title: Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.
Authors: Korkmaz, B. / Lesner, A. / Wysocka, M. / Gieldon, A. / Hakansson, M. / Gauthier, F. / Logan, D.T. / Jenne, D.E. / Lauritzen, C. / Pedersen, J.
History
DepositionDec 2, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dipeptidyl peptidase 1
B: Dipeptidyl peptidase 1
C: Dipeptidyl peptidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,4948
Polymers39,7143
Non-polymers1,7805
Water5,332296
1
A: Dipeptidyl peptidase 1
B: Dipeptidyl peptidase 1
C: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
B: Dipeptidyl peptidase 1
C: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
B: Dipeptidyl peptidase 1
C: Dipeptidyl peptidase 1
hetero molecules

A: Dipeptidyl peptidase 1
B: Dipeptidyl peptidase 1
C: Dipeptidyl peptidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,97532
Polymers158,85512
Non-polymers7,12020
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area51830 Å2
ΔGint-230 kcal/mol
Surface area52790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.690, 87.770, 115.030
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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Dipeptidyl peptidase ... , 3 types, 3 molecules ABC

#1: Protein Dipeptidyl peptidase 1 / Cathepsin C / Cathepsin C / Cathepsin J / Dipeptidyl peptidase I / DPPI / Dipeptidyl transferase


Mass: 13500.163 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSC, CPPI / Cell line (production host): BTI-TN-5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P53634, dipeptidyl-peptidase I
#2: Protein Dipeptidyl peptidase 1 / Cathepsin C / Cathepsin C / Cathepsin J / Dipeptidyl peptidase I / DPPI / Dipeptidyl transferase


Mass: 18630.018 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSC, CPPI / Cell line (production host): BTI-TN-5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P53634, dipeptidyl-peptidase I
#3: Protein Dipeptidyl peptidase 1 / Cathepsin C / Cathepsin C / Cathepsin J / Dipeptidyl peptidase I / DPPI / Dipeptidyl transferase


Mass: 7583.444 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSC, CPPI / Cell line (production host): BTI-TN-5B1-4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P53634, dipeptidyl-peptidase I

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Sugars , 2 types, 3 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_d2-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+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 / 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

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Non-polymers , 3 types, 298 molecules

#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-H9B / (2~{S})-~{N}-[(1~{R},2~{R})-1-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenyl]phenyl]cyclopropyl]-2-azanyl-butanamide


Mass: 391.430 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C21H24F3N3O / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 296 / 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: 2.79 Å3/Da / Density % sol: 55.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 20.0 % (w/v) PEG 6000 0.1 M sodium citrate pH 5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-2 / Wavelength: 1.03796 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 10, 2009
RadiationMonochromator: DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03796 Å / Relative weight: 1
ReflectionResolution: 1.898→28.026 Å / Num. obs: 34042 / % possible obs: 97.2 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.4
Reflection shellResolution: 1.898→1.95 Å / Rmerge(I) obs: 0.394 / Mean I/σ(I) obs: 3.4 / % possible all: 96

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Processing

Software
NameVersionClassification
REFMAC5.8.0238 2018/15/10refinement
XDSdata reduction
XDSdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: in-house structure

Resolution: 1.898→28.026 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.952 / SU B: 5.154 / SU ML: 0.077 / Cross valid method: THROUGHOUT / ESU R: 0.116 / ESU R Free: 0.114 / Details: Hydrogens were added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1858 1684 -
Rwork0.147 --
all0.149 --
obs-34042 97.18 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.472 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å20 Å2
2--1.623 Å20 Å2
3----2.013 Å2
Refinement stepCycle: LAST / Resolution: 1.898→28.026 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2760 0 118 296 3174
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0132998
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172567
X-RAY DIFFRACTIONr_angle_refined_deg1.8431.7044094
X-RAY DIFFRACTIONr_angle_other_deg1.4511.6245979
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.3775351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.48322.838148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.30915438
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.3781511
X-RAY DIFFRACTIONr_chiral_restr0.0920.2390
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023345
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02672
X-RAY DIFFRACTIONr_nbd_refined0.2120.2583
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.22490
X-RAY DIFFRACTIONr_nbtor_refined0.1840.21463
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.21338
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1940.2231
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1320.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2990.211
X-RAY DIFFRACTIONr_nbd_other0.2430.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1970.216
X-RAY DIFFRACTIONr_mcbond_it1.5811.8571401
X-RAY DIFFRACTIONr_mcbond_other1.5811.8571400
X-RAY DIFFRACTIONr_mcangle_it2.4742.7731750
X-RAY DIFFRACTIONr_mcangle_other2.4742.7731751
X-RAY DIFFRACTIONr_scbond_it1.7282.0881597
X-RAY DIFFRACTIONr_scbond_other1.7282.0891598
X-RAY DIFFRACTIONr_scangle_it2.7353.0752340
X-RAY DIFFRACTIONr_scangle_other2.7353.0752341
X-RAY DIFFRACTIONr_lrange_it5.59323.2873484
X-RAY DIFFRACTIONr_lrange_other5.59323.2963485
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)WRfactor Rwork
1.898-1.9480.2221170.1962319254095.90550.163
1.948-2.0010.211100.1822366250298.96080.145
2.001-2.0580.2081130.1682294242999.09430.134
2.058-2.1210.1891200.1662180232498.96730.135
2.121-2.190.2021130.152112225998.49490.122
2.19-2.2670.1781020.1512077220898.68660.123
2.267-2.3520.1821030.1332016214798.69590.106
2.352-2.4470.1851200.1421892204598.38630.113
2.447-2.5550.171020.1371849198998.08950.111
2.555-2.6790.183920.1361742187797.70910.11
2.679-2.8220.195910.1441674181497.29880.12
2.822-2.9910.208790.1381577170597.12610.118
2.991-3.1950.176670.1381500161896.8480.121
3.195-3.4480.179730.1431377150296.53790.132
3.448-3.7710.165650.1361267138895.96540.129
3.771-4.2070.168610.1231143128193.98910.12
4.207-4.8390.143550.1261017113194.78340.124
4.839-5.8830.246440.16286296593.8860.159
5.883-8.1420.195360.17669178392.8480.17
8.142-28.0260.214210.20440349585.65660.221
Refinement TLS params.

Details: U values: with tls added / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3668-0.17750.27041.26080.03141.22960.01230.02480.0749-0.0717-0.02360.1315-0.1641-0.10840.01140.07830.028-0.00260.02170.02520.0966-6.804-25.438-20.223
20.9860.1147-0.02561.41270.28550.8877-0.00870.0155-0.0381-0.05080.0145-0.1333-0.09340.1502-0.00580.0305-0.02180.02120.03760.01680.07917.363-30.999-18.042
31.01250.0245-0.01460.81750.30721.19190.0186-0.10870.06890.0719-0.0004-0.1243-0.18190.2678-0.01830.0512-0.0508-0.00120.07850.0080.074420.197-24.707-8.984
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLA1 - 118
2X-RAY DIFFRACTION2ALLB206 - 367
3X-RAY DIFFRACTION3ALLC372 - 439

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