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- PDB-6qbs: The Alkyne Moiety as a Latent Electrophile in Irreversible Covale... -

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Basic information

Entry
Database: PDB / ID: 6qbs
TitleThe Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K
ComponentsCathepsin K
KeywordsHYDROLASE / Covalent Inhibitor / Cathepsin K
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 / Collagen degradation / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / cysteine-type peptidase activity / positive regulation of apoptotic signaling pathway / bone resorption / cellular response to transforming growth factor beta stimulus / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / proteolysis involved in protein catabolic process / lysosomal lumen / 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 / serine-type endopeptidase activity / intracellular membrane-bounded organelle / 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 proteinases / Cysteine peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cathepsin B; Chain A / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-HVW / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMons, E. / Jansen, I.D.C. / Loboda, J. / van Doodewaerd, B.R. / Verdoes, M. / van Boeckel, C.A.A. / van Veelen, P.A. / Turk, B. / Turk, D. / Hermans, J. / Ovaa, H.
Funding support Slovenia, Netherlands, 2items
OrganizationGrant numberCountry
Slovenian Research Agency Slovenia
Netherlands Organisation for Scientific Research Netherlands
CitationJournal: J. Am. Chem. Soc. / Year: 2019
Title: The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.
Authors: Mons, E. / Jansen, I.D.C. / Loboda, J. / van Doodewaerd, B.R. / Hermans, J. / Verdoes, M. / van Boeckel, C.A.A. / van Veelen, P.A. / Turk, B. / Turk, D. / Ovaa, H.
History
DepositionDec 21, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 6, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 3, 2019Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.3Jan 24, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)48,1237
Polymers47,0472
Non-polymers1,0765
Water11,728651
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1430 Å2
ΔGint-26 kcal/mol
Surface area18850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.35, 75.35, 340.20
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 23523.480 Da / Num. of mol.: 2
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: Chemical ChemComp-HVW / (2~{S})-4-methyl-~{N}-prop-2-enyl-2-[[(1~{S})-2,2,2-tris(fluoranyl)-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide


Mass: 482.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29F3N2O3S
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 651 / 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: 2.96 Å3/Da / Density % sol: 58.49 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / Details: 0.2 M CaCl2, 20 % PEG-3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.7→47.09 Å / Num. obs: 64186 / % possible obs: 99.9 % / Redundancy: 33.1 % / CC1/2: 0.998 / Rrim(I) all: 0.177 / Net I/σ(I): 16.3
Reflection shellResolution: 1.7→1.75 Å

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Processing

Software
NameClassification
MAINrefinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FTD

2ftd


Resolution: 1.7→47.09 Å / Cor.coef. Fo:Fc: 0.9475 / Cor.coef. Fo:Fc free: 0.9449 / Cross valid method: NONE / σ(F): 0 / Phase error: 19
RfactorNum. reflection% reflectionSelection details
Rfree0.2102 --NONE
Rwork0.2043 ---
all0.2043 ---
obs0.2043 64031 100 %-
Solvent computationBsol: 20.32 Å2 / ksol: 0.36 e/Å3
Displacement parametersBiso max: 83.91 Å2 / Biso mean: 19.34 Å2 / Biso min: 5.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.239 Å20.025 Å20 Å2
2--0.239 Å20 Å2
3----0.478 Å2
Refinement stepCycle: LAST / Resolution: 1.7→47.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3298 0 69 651 4018
LS refinement shellResolution: 1.7→1.73 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2778 3091 100 %
Rwork0.2687 3091 -
all-3091 -
obs-3091 1 %

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