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- PDB-4dmy: Cathepsin K inhibitor -

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Basic information

Entry
Database: PDB / ID: 4dmy
TitleCathepsin K inhibitor
ComponentsCathepsin K
KeywordsHydrolase/Hydrolase inhibitor / Cathepsin K inhibitor / osteoarthritis / 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 / 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-0LC / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsDossetter, A.G. / Beeley, H. / Bowyer, J. / Cook, C.R. / Crawford, J.J. / Finlayson, J.E. / Heron, N.M. / Heyes, C. / Highton, A.J. / Hudson, J.A. ...Dossetter, A.G. / Beeley, H. / Bowyer, J. / Cook, C.R. / Crawford, J.J. / Finlayson, J.E. / Heron, N.M. / Heyes, C. / Highton, A.J. / Hudson, J.A. / Kenny, P.W. / Martin, S. / MacFaul, P.A. / McGuire, T.M. / Gutierrez, P.M. / Morley, A.D. / Morris, J.J. / Page, K.M. / Rosenbrier Ribeiro, L. / Sawney, H. / Steinbacher, S. / Krapp, S. / Jestel, A. / Smith, C. / Vickers, M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the ...Title: (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the treatment of osteoarthritis.
Authors: Dossetter, A.G. / Beeley, H. / Bowyer, J. / Cook, C.R. / Crawford, J.J. / Finlayson, J.E. / Heron, N.M. / Heyes, C. / Highton, A.J. / Hudson, J.A. / Jestel, A. / Kenny, P.W. / Krapp, S. / ...Authors: Dossetter, A.G. / Beeley, H. / Bowyer, J. / Cook, C.R. / Crawford, J.J. / Finlayson, J.E. / Heron, N.M. / Heyes, C. / Highton, A.J. / Hudson, J.A. / Jestel, A. / Kenny, P.W. / Krapp, S. / Martin, S. / MacFaul, P.A. / McGuire, T.M. / Gutierrez, P.M. / Morley, A.D. / Morris, J.J. / Page, K.M. / Ribeiro, L.R. / Sawney, H. / Steinbacher, S. / Smith, C. / Vickers, M.
History
DepositionFeb 8, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Nov 26, 2014Group: Structure summary
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name

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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)48,3409
Polymers47,0472
Non-polymers1,2937
Water9,008500
1
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,1244
Polymers23,5231
Non-polymers6013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2165
Polymers23,5231
Non-polymers6934
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)31.927, 69.554, 90.645
Angle α, β, γ (deg.)90.00, 99.83, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 23523.480 Da / Num. of mol.: 2 / Fragment: unp residues 115-329
Source method: isolated from a genetically manipulated source
Details: refolding from inclusion bodies / Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Escherichia coli (E. coli) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-0LC / (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide


Mass: 408.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H25FN4O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 500 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE LIGAND 0LC IS COVALENTLY BOUND TO SIDE CHAIN OF RESIDUES CYS 25. THE STARTING LIGAND GENERATING ...THE LIGAND 0LC IS COVALENTLY BOUND TO SIDE CHAIN OF RESIDUES CYS 25. THE STARTING LIGAND GENERATING THE FINAL PRODUCT 0LC HAD A TRIPLE BOND BETWEEN C29 AND N30 ATOM GROUPS.

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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: 41.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.5 / Details: PEG, pH 5.5, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.90005 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 24, 2006 / Details: Rh coated meridionally focussing mirror
RadiationMonochromator: Fixed-exit LN2 cooled Double Crystal Monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.90005 Å / Relative weight: 1
ReflectionResolution: 1.63→54.9 Å / Num. all: 47594 / Num. obs: 47594 / % possible obs: 97.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.2 % / Biso Wilson estimate: 19.978 Å2 / Rsym value: 0.079 / Net I/σ(I): 11
Reflection shellResolution: 1.63→1.7 Å / Redundancy: 2.8 % / Num. unique all: 5060 / Rsym value: 0.354 / % possible all: 87.7

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Processing

Software
NameVersionClassification
MAR345data collection
MOLREPphasing
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.63→54.88 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.949 / SU B: 4.123 / SU ML: 0.064 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.137 / ESU R Free: 0.094 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19008 2380 5 %RANDOM
Rwork0.12774 ---
all0.1301 47594 --
obs0.13086 45211 97.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 13.735 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å2-0.51 Å2
2--1.49 Å20 Å2
3----1.7 Å2
Refinement stepCycle: LAST / Resolution: 1.63→54.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3298 0 86 500 3884
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0223538
X-RAY DIFFRACTIONr_bond_other_d0.0010.022431
X-RAY DIFFRACTIONr_angle_refined_deg1.2191.9724795
X-RAY DIFFRACTIONr_angle_other_deg0.9373.0045912
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2275444
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.97125160
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.95415586
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.1541516
X-RAY DIFFRACTIONr_chiral_restr0.0750.2479
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024006
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02698
X-RAY DIFFRACTIONr_nbd_refined0.2080.2742
X-RAY DIFFRACTIONr_nbd_other0.190.22613
X-RAY DIFFRACTIONr_nbtor_refined0.1820.21748
X-RAY DIFFRACTIONr_nbtor_other0.0840.21800
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2328
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2540.221
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1510.257
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1520.232
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.98422818
X-RAY DIFFRACTIONr_mcbond_other1.2722906
X-RAY DIFFRACTIONr_mcangle_it3.55433441
X-RAY DIFFRACTIONr_scbond_it5.01441704
X-RAY DIFFRACTIONr_scangle_it5.9961346
X-RAY DIFFRACTIONr_rigid_bond_restr2.54337551
X-RAY DIFFRACTIONr_sphericity_free10.2183500
X-RAY DIFFRACTIONr_sphericity_bonded4.19735880
LS refinement shellResolution: 1.632→1.675 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.264 156 -
Rwork0.152 2965 -
obs--86.84 %

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