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- PDB-6ql8: Cathepsin-K in complex with MIV-711 -

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Basic information

Entry
Database: PDB / ID: 6ql8
TitleCathepsin-K in complex with MIV-711
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-J5N / NITRATE ION / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 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
DepositionJan 31, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 16, 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

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6798
Polymers23,7381
Non-polymers9427
Water4,684260
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint10 kcal/mol
Surface area10150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.910, 70.910, 54.270
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: 23737.727 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-J5N / ~{N}-[(2~{S})-1-[(3~{R},3~{a}~{R},6~{R},6~{a}~{R})-6-ethynyl-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-[5-fluoranyl-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide


Mass: 569.691 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H36FN5O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / 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: 2.87 Å3/Da / Density % sol: 57.2 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100mM ADA pH6.0, 500mM ammonium nitrate, 17% PEG 3350
PH range: 6.0-6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 11, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 1.8→70.91 Å / Num. obs: 24605 / % possible obs: 98.1 % / Redundancy: 3.9 % / CC1/2: 0.992 / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.067 / Rrim(I) all: 0.136 / Net I/σ(I): 8.5 / Num. measured all: 96143 / Scaling rejects: 8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.8-1.843.30.70311800.5550.4240.82481.7
9-70.913.70.0342170.9980.0190.03998.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimless0.5.32data scaling
PHASERphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→70.91 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.947 / SU B: 4.158 / SU ML: 0.066 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.099 / ESU R Free: 0.098
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1811 1263 5.1 %RANDOM
Rwork0.149 ---
obs0.1506 23335 97.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.3 Å
Displacement parametersBiso max: 65.3 Å2 / Biso mean: 17.394 Å2 / Biso min: 8.23 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0 Å2-0 Å2
2--0.01 Å2-0 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 1.8→70.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1664 0 64 260 1988
Biso mean--19.79 28.36 -
Num. residues----217
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.021786
X-RAY DIFFRACTIONr_bond_other_d0.0020.021583
X-RAY DIFFRACTIONr_angle_refined_deg1.3671.9812410
X-RAY DIFFRACTIONr_angle_other_deg0.8983.0013700
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4435221
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.3312580
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.20715296
X-RAY DIFFRACTIONr_dihedral_angle_4_deg7.143158
X-RAY DIFFRACTIONr_chiral_restr0.0770.2241
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022022
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02354
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 74 -
Rwork0.286 1442 -
all-1516 -
obs--82.12 %
Refinement TLS params.Method: refined / Origin x: 27.944 Å / Origin y: 13.763 Å / Origin z: 26.661 Å
111213212223313233
T0.023 Å2-0.002 Å20.0049 Å2-0.0105 Å2-0.0092 Å2--0.0208 Å2
L0.8095 °2-0.4493 °20.1926 °2-1.1966 °2-0.4278 °2--1.0878 °2
S-0.0146 Å °0.006 Å °0.018 Å °0.0656 Å °0.0049 Å °0.0613 Å °-0.0408 Å °-0.061 Å °0.0097 Å °

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