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- PDB-7qbo: Structure of the activation intermediate of cathepsin K in comple... -

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Basic information

Entry
Database: PDB / ID: 7qbo
TitleStructure of the activation intermediate of cathepsin K in complex with the azadipeptide nitrile inhibitor Gu1303
Components(Cathepsin K) x 2
KeywordsHYDROLASE / Cathepsin K / Protease inhibitor / Cyanohydrazide warhead / Azadipeptide nitrile
Function / homology
Function and homology information


cathepsin K / mononuclear cell differentiation / intramembranous ossification / negative regulation of cartilage development / cellular response to zinc ion starvation / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / thyroid hormone generation / endolysosome lumen / Trafficking and processing of endosomal TLR / proteoglycan binding ...cathepsin K / mononuclear cell differentiation / intramembranous ossification / negative regulation of cartilage development / cellular response to zinc ion starvation / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / thyroid hormone generation / endolysosome lumen / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / cysteine-type endopeptidase activator activity involved in apoptotic process / mitophagy / fibronectin binding / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / cysteine-type peptidase activity / bone resorption / cellular response to transforming growth factor beta stimulus / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / lysosomal lumen / proteolysis involved in protein catabolic process / positive regulation of apoptotic signaling pathway / response to insulin / response to organic cyclic compound / cellular response to tumor necrosis factor / response to ethanol / lysosome / immune response / apical plasma membrane / external side of plasma membrane / cysteine-type endopeptidase activity / intracellular membrane-bounded organelle / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular region / nucleoplasm
Similarity search - Function
Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / : / 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 ...Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / : / 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 peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
Chem-9ZG / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBenysek, J. / Busa, M. / Mares, M.
Funding support Czech Republic, 2items
OrganizationGrant numberCountry
European Regional Development FundChemBioDrug CZ.02.1.01/0.0/0.0/16_019/0000729 Czech Republic
Czech Academy of SciencesRVO 61388963 Czech Republic
CitationJournal: J Enzyme Inhib Med Chem / Year: 2022
Title: Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.
Authors: Benysek, J. / Busa, M. / Rubesova, P. / Fanfrlik, J. / Lepsik, M. / Brynda, J. / Matouskova, Z. / Bartz, U. / Horn, M. / Gutschow, M. / Mares, M.
History
DepositionNov 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._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_PubMed / _citation.title / _citation.year
Revision 2.0Jan 18, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / cell ...atom_site / cell / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_asym / struct_conf / struct_conn / struct_ref / struct_ref_seq / struct_sheet_range
Item: _atom_site.label_entity_id / _atom_site.label_seq_id ..._atom_site.label_entity_id / _atom_site.label_seq_id / _cell.Z_PDB / _pdbx_entity_nonpoly.entity_id / _pdbx_nonpoly_scheme.entity_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_asym.entity_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.ref_id / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
P: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2768
Polymers32,6602
Non-polymers6166
Water5,206289
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2780 Å2
ΔGint-18 kcal/mol
Surface area13480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.214, 103.214, 54.985
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11P-568-

HOH

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Components

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Protein , 2 types, 2 molecules AP

#1: Protein Cathepsin K / Cathepsin O / Cathepsin O2 / Cathepsin X


Mass: 23680.674 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P43235, cathepsin K
#2: Protein Cathepsin K / Cathepsin O / Cathepsin O2 / Cathepsin X


Mass: 8979.196 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P43235, cathepsin K

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Non-polymers , 5 types, 295 molecules

#3: Chemical ChemComp-9ZG / (phenylmethyl) ~{N}-[(2~{S})-1-[[aminomethyl(methyl)amino]-methyl-amino]-1-oxidanylidene-3-phenyl-propan-2-yl]carbamate


Mass: 370.445 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 289 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.07 Å3/Da / Density % sol: 40.72 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 10% PEG 8000, 20% ethylene glycol, 0.02 M sodium L-glutamate, 0.02 M DL-alanine, 0.02 M glycine, 0.02 M DL-lysine HCl, 0.02 M DL-serine, 0.1M MES/imidazole pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.9→46.2 Å / Num. obs: 23911 / % possible obs: 99.8 % / Redundancy: 7.894 % / Biso Wilson estimate: 27.475 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.111 / Rrim(I) all: 0.118 / Χ2: 1.077 / Net I/σ(I): 13.34 / Num. measured all: 188744
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.9-2.027.4940.632.8628199378937630.8530.67799.3
2.02-2.158.2130.3924.9929345357435730.9460.418100
2.15-2.337.8880.2647.126363334433420.9710.28399.9
2.33-2.558.2740.1919.8125442307630750.9860.204100
2.55-2.857.8060.13513.321981281828160.9920.14599.9
2.85-3.298.1970.08919.8420418249124910.9970.095100
3.29-4.027.8230.0628.816717213721370.9980.065100
4.02-5.677.6460.05232.3612968169716960.9980.05699.9
5.67-46.27.1820.0532.67311102310180.9980.05499.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
PDB_EXTRACT3.27data extraction
XDSdata scaling
BUCCANEERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7NXM

7nxm


Resolution: 1.9→46.2 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.933 / SU B: 3.416 / SU ML: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.145 / ESU R Free: 0.138 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2116 1196 5 %RANDOM
Rwork0.1643 ---
obs0.1667 22715 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.12 Å2 / Biso mean: 23.299 Å2 / Biso min: 12.18 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å20 Å2
2---0.4 Å20 Å2
3---0.81 Å2
Refinement stepCycle: final / Resolution: 1.9→46.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 41 293 2543
Biso mean--29.75 33.29 -
Num. residues----283
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132340
X-RAY DIFFRACTIONr_bond_other_d0.0020.0182149
X-RAY DIFFRACTIONr_angle_refined_deg1.5031.6423163
X-RAY DIFFRACTIONr_angle_other_deg1.4131.5884941
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6825293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.20623130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.07215393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5721512
X-RAY DIFFRACTIONr_chiral_restr0.0730.2285
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022735
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02569
LS refinement shellResolution: 1.901→1.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 86 -
Rwork0.255 1633 -
all-1719 -
obs--98.51 %

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