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- PDB-5tdi: Crystal structure of Cathepsin K with a covalently-linked inhibit... -

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Basic information

Entry
Database: PDB / ID: 5tdi
TitleCrystal structure of Cathepsin K with a covalently-linked inhibitor at 1.4 Angstrom resolution.
ComponentsCathepsin K
KeywordsHYDROLASE/HYDROLASE INHIBITOR / cathepsin K / covalent / inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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 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-7AS / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsLaw, S. / Aguda, A. / Nguyen, N. / Brayer, G. / Bromme, D.
Funding support Canada, 2items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)MOP89974 Canada
Canadian Institutes of Health Research (CIHR)MOP201209 Canada
CitationJournal: Biochem. J. / Year: 2017
Title: Identification of mouse cathepsin K structural elements that regulate the potency of odanacatib.
Authors: Law, S. / Andrault, P.M. / Aguda, A.H. / Nguyen, N.T. / Kruglyak, N. / Brayer, G.D. / Bromme, D.
History
DepositionSep 19, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2017Group: Structure summary
Revision 1.2Mar 8, 2017Group: Database references
Revision 1.3Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.4Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: 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 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0352
Polymers23,5071
Non-polymers5281
Water5,008278
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.249, 54.620, 80.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 23507.480 Da / Num. of mol.: 1 / Mutation: S49A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella pastoris GS115 (fungus) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-7AS / 4-fluoro-N-{1-[(Z)-iminomethyl]cyclopropyl}-N~2~-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]ethyl }-L-leucinamide / covalently linked Odanacatib


Mass: 527.575 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29F4N3O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.11 Å3/Da / Density % sol: 41.68 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.05 M cadmium sulfate hydrate, 0.1 M HEPES pH 7.5, 1.0 M sodium acetate trihydrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 15, 2016
RadiationMonochromator: Si(111) and Si(220) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.4→45.162 Å / Num. obs: 39625 / % possible obs: 99.3 % / Redundancy: 5.4 % / CC1/2: 0.986 / Rmerge(I) obs: 0.132 / Net I/σ(I): 8.1
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 3.7 / CC1/2: 0.897 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX1.8.1_1168refinement
iMOSFLM7.2.1data reduction
SCALA3.3.22data scaling
PHENIX1.8.1_1168phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X6H

4x6h


Resolution: 1.4→45.162 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.63
RfactorNum. reflection% reflection
Rfree0.1705 1939 4.9 %
Rwork0.1427 --
obs0.144 39559 99.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 15.2 Å2
Refinement stepCycle: LAST / Resolution: 1.4→45.162 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1648 0 36 278 1962
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071737
X-RAY DIFFRACTIONf_angle_d1.0182347
X-RAY DIFFRACTIONf_dihedral_angle_d13.678635
X-RAY DIFFRACTIONf_chiral_restr0.072235
X-RAY DIFFRACTIONf_plane_restr0.004307
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.4350.25771400.15772651X-RAY DIFFRACTION99
1.435-1.47380.19451420.14572665X-RAY DIFFRACTION99
1.4738-1.51720.20371260.13972657X-RAY DIFFRACTION99
1.5172-1.56620.2081340.1332604X-RAY DIFFRACTION98
1.5662-1.62220.19461520.12872654X-RAY DIFFRACTION99
1.6222-1.68710.18481340.12682663X-RAY DIFFRACTION99
1.6871-1.76390.17381400.12752676X-RAY DIFFRACTION99
1.7639-1.85690.17151370.13062649X-RAY DIFFRACTION99
1.8569-1.97320.19021330.13162668X-RAY DIFFRACTION98
1.9732-2.12560.17661450.13342686X-RAY DIFFRACTION99
2.1256-2.33950.16351440.13412715X-RAY DIFFRACTION100
2.3395-2.6780.1611420.14942728X-RAY DIFFRACTION99
2.678-3.37380.14931420.15272717X-RAY DIFFRACTION98
3.3738-45.18590.15111280.15472887X-RAY DIFFRACTION99

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