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- PDB-6qlx: Cathepsin-K in complex with fluoro-oxa-azabicyclo[3.3.0]octanyl c... -

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Basic information

Entry
Database: PDB / ID: 6qlx
TitleCathepsin-K in complex with fluoro-oxa-azabicyclo[3.3.0]octanyl containing inhibitor
ComponentsCathepsin K
KeywordsHYDROLASE / inhibitor complex / lysosomal cysteine proteinase
Function / homology
Function and homology information


cathepsin K / negative regulation of cartilage development / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / Collagen degradation / collagen catabolic process ...cathepsin K / negative regulation of cartilage development / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / Collagen degradation / collagen catabolic process / fibronectin binding / extracellular matrix disassembly / bone resorption / mitophagy / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / lysosome / apical plasma membrane / external side of plasma membrane / serine-type endopeptidase activity / cysteine-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-HKH / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsDerbyshire, D.J.
CitationJournal: To Be Published
Title: Successful development of 3-oxohexahydrofuropyrrole amino acid amides as inhibitors of Cathepsin-K.
Authors: Derbyshire, D.J.
History
DepositionFeb 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,1272
Polymers23,6811
Non-polymers4471
Water6,125340
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.204, 71.204, 54.541
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

#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 / Plasmid: pET16b / Production host: Escherichia coli (E. coli) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-HKH / ~{N}-[(2~{S})-1-[(3~{R},3~{a}~{R},6~{S},6~{a}~{S})-6-fluoranyl-3-oxidanyl-2,3,3~{a},5,6,6~{a}-hexahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxidanylidene-pentan-2-yl]-4-thiophen-2-yl-benzamide


Mass: 446.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27FN2O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.92 Å3/Da / Density % sol: 57.87 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.1
Details: 25mM ADA pH6.1, 400mM sodium chloride and 20% PEG 5k.mme
PH range: 6.0 - 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Type: SRS / Wavelength: 1.488 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 19, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.488 Å / Relative weight: 1
ReflectionResolution: 2.1→71.2 Å / Num. obs: 14341 / % possible obs: 89.5 % / Redundancy: 3.6 % / CC1/2: 0.957 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.063 / Rrim(I) all: 0.12 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.1-2.162.30.1617340.9490.1210.20354.4
8.66-71.23.50.1012460.9660.0610.11897.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.51 Å37 Å
Translation5.51 Å37 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimless0.6.2data scaling
PHASER2.8.2phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→71.2 Å / Cor.coef. Fo:Fc: 0.887 / Cor.coef. Fo:Fc free: 0.862 / SU B: 7.366 / SU ML: 0.096 / SU R Cruickshank DPI: 0.2541 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.254 / ESU R Free: 0.205
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 731 5.1 %RANDOM
Rwork0.1858 ---
obs0.1885 13578 89.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 83.9 Å2 / Biso mean: 22.475 Å2 / Biso min: 10.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å2-0 Å2
2--0.12 Å2-0 Å2
3----0.23 Å2
Refinement stepCycle: final / Resolution: 2.1→71.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1654 0 31 340 2025
Biso mean--17.3 37.97 -
Num. residues----216
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0191751
X-RAY DIFFRACTIONr_bond_other_d0.0020.021560
X-RAY DIFFRACTIONr_angle_refined_deg1.4851.9682371
X-RAY DIFFRACTIONr_angle_other_deg0.983.0013649
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9355223
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.75325.1979
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.04515293
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.329157
X-RAY DIFFRACTIONr_chiral_restr0.0890.2242
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021992
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02353
LS refinement shellResolution: 2.1→2.155 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.238 34 -
Rwork0.127 583 -
all-617 -
obs--52.96 %
Refinement TLS params.

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)
11.0044-0.3804-0.3240.41090.11630.45910.01740.04140.0410.0472-0.01440.0061-0.0242-0.0019-0.00310.03270.0012-0.00440.03910.00010.03121.73877.391-10.9173
20.6236-0.2767-0.28351.3180.47261.1692-0.0150.0281-0.0226-0.0340.03610.0219-0.0046-0.0058-0.02110.0056-0.0113-0.01060.02670.01820.050822.19285.6525-11.1028
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 215
2X-RAY DIFFRACTION1I1
3X-RAY DIFFRACTION2W1 - 999

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