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- PDB-6ic7: Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile ... -

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Basic information

Entry
Database: PDB / ID: 6ic7
TitleHuman cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3
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 / MHC class II antigen presentation / endoplasmic reticulum-Golgi intermediate compartment membrane / : / 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 / 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-H9H / Dipeptidyl peptidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 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.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 / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.type_symbol / _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

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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)41,2978
Polymers39,3863
Non-polymers1,9105
Water6,287349
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)165,18632
Polymers157,54512
Non-polymers7,64120
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 area51750 Å2
ΔGint-227 kcal/mol
Surface area53110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.365, 87.549, 115.004
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 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 J / Dipeptidyl peptidase I / DPPI / Dipeptidyl transferase


Mass: 18302.613 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 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


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, 351 molecules

#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-H9H / 1-azanyl-~{N}-[(1~{R},2~{R})-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]cyclohexane-1-carboxamide


Mass: 521.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H35N5O3S / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 55.94 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 20.0 % (w/v) PEG 3000 0.2 M ammonium citrate dibasic 2.5 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER X8 PROTEUM / Wavelength: 1.5418 Å
DetectorType: Bruker Platinum 135 / Detector: CCD / Date: Dec 1, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→28.3 Å / Num. obs: 30537 / % possible obs: 98.2 % / Redundancy: 11.5 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 23.8
Reflection shellResolution: 2→2.1 Å / Rmerge(I) obs: 0.164 / Mean I/σ(I) obs: 6.1 / % possible all: 85.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0238 2018/15/10refinement
PROTEUMdata reduction
PROTEUMdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→28.231 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.94 / SU B: 4.767 / SU ML: 0.085 / Cross valid method: THROUGHOUT / ESU R: 0.155 / ESU R Free: 0.144
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2034 1466 -
Rwork0.1596 --
all0.162 --
obs-29338 97.252 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 20.023 Å2
Baniso -1Baniso -2Baniso -3
1-0.146 Å20 Å20 Å2
2--0.417 Å20 Å2
3----0.563 Å2
Refinement stepCycle: LAST / Resolution: 2→28.231 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2759 0 127 349 3235
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0133061
X-RAY DIFFRACTIONr_bond_other_d0.0020.0182619
X-RAY DIFFRACTIONr_angle_refined_deg1.9311.7094195
X-RAY DIFFRACTIONr_angle_other_deg1.4621.6336113
X-RAY DIFFRACTIONr_dihedral_angle_1_deg19.055.346376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.53622.933150
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.67415436
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg4.877153
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.7571511
X-RAY DIFFRACTIONr_chiral_restr0.0910.2403
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023705
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02691
X-RAY DIFFRACTIONr_nbd_refined0.2290.2634
X-RAY DIFFRACTIONr_symmetry_nbd_other0.190.22602
X-RAY DIFFRACTIONr_nbtor_refined0.1840.21489
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0930.21337
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2120.2297
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0930.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2440.219
X-RAY DIFFRACTIONr_nbd_other0.2160.267
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.330.222
X-RAY DIFFRACTIONr_mcbond_it1.3961.4011424
X-RAY DIFFRACTIONr_mcbond_other1.3951.41423
X-RAY DIFFRACTIONr_mcangle_it2.3492.0921786
X-RAY DIFFRACTIONr_mcangle_other2.3492.0931787
X-RAY DIFFRACTIONr_scbond_it1.3581.5741637
X-RAY DIFFRACTIONr_scbond_other1.3581.5751638
X-RAY DIFFRACTIONr_scangle_it2.2252.3182401
X-RAY DIFFRACTIONr_scangle_other2.2252.3192402
X-RAY DIFFRACTIONr_lrange_it5.59918.0883671
X-RAY DIFFRACTIONr_lrange_other5.60118.0853671
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
2-2.0520.202750.1851741216583.87990.161
2.052-2.1080.2551000.1891862215491.08630.165
2.108-2.1680.2461040.1751914208596.78660.153
2.168-2.2350.213930.1711906202498.76480.148
2.235-2.3070.2181030.1591809193498.86250.14
2.307-2.3880.231880.1631782189498.73280.144
2.388-2.4770.2291050.1641728184999.13470.146
2.477-2.5780.2091010.1441671178799.16060.132
2.578-2.6910.16790.1491581167299.28230.138
2.691-2.8210.239880.1631564166599.21920.156
2.821-2.9720.209720.1551428151299.20630.152
2.972-3.150.167670.1551408149298.86060.155
3.15-3.3650.22650.1651313138899.27950.17
3.365-3.630.22650.1651227130299.23190.175
3.63-3.970.161670.1391128120998.8420.153
3.97-4.4280.167490.1311038109499.36010.153
4.428-5.0920.136450.12390995699.79080.151
5.092-6.1860.22440.17680484999.88220.199
6.186-8.5460.246350.19164067699.85210.226
8.546-28.2310.266210.23940843199.5360.305
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)
11.6197-0.03830.47641.25510.16481.2324-0.01070.00250.0879-0.0938-0.02110.1128-0.1275-0.10080.03180.03370.01980.00130.02140.01750.0446-6.84-25.289-20.185
21.13030.0273-0.06891.26790.20740.8449-0.0148-0.0109-0.0433-0.00440.0004-0.1286-0.04780.13790.01450.0049-0.00860.00060.02980.01610.035717.601-30.779-17.978
30.96050.0522-0.16371.25730.38841.17130.019-0.15690.07320.12780.0034-0.1607-0.12280.2362-0.02230.0792-0.0386-0.01910.11310.01140.070720.239-24.406-8.854
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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