+Open data
-Basic information
Entry | Database: PDB / ID: 4dmx | ||||||
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Title | Cathepsin K inhibitor | ||||||
Components | Cathepsin K | ||||||
Keywords | Hydrolase/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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å | ||||||
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. ...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. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4dmx.cif.gz | 95.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4dmx.ent.gz | 77.7 KB | Display | PDB format |
PDBx/mmJSON format | 4dmx.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dm/4dmx ftp://data.pdbj.org/pub/pdb/validation_reports/dm/4dmx | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 23523.480 Da / Num. of mol.: 1 / 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 |
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#2: Chemical | ChemComp-0LB / ( |
#3: Chemical | ChemComp-GOL / |
#4: Water | ChemComp-HOH / |
Nonpolymer details | THE LIGAND 0LB IS COVALENTLY BOUND TO THE SIDE CHAIN OF CYS 25. THE STARTING LIGAND GENERATING THE ...THE LIGAND 0LB IS COVALENTLY |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 1.95 Å3/Da / Density % sol: 37.06 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion / pH: 5.5 / Details: PEG, pH 5.5, VAPOR DIFFUSION, temperature 293K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.037 Å |
Detector | Type: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 27, 2006 Details: Liquid nitrogen cooled channel-cut silicon monochromator and a cylindrical grazing incidence mirror |
Radiation | Monochromator: high resolution Si(311) cut and a lower resolution Si(111) cut Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.037 Å / Relative weight: 1 |
Reflection | Resolution: 1.7→83 Å / Num. all: 19225 / Num. obs: 19225 / % possible obs: 96.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.3 % / Biso Wilson estimate: 19.878 Å2 / Rsym value: 0.123 / Net I/σ(I): 3.2 |
Reflection shell | Resolution: 1.7→1.79 Å / Redundancy: 2.3 % / Num. unique all: 2344 / Rsym value: 0.56 / % possible all: 81 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→83 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.95 / SU B: 5.124 / SU ML: 0.084 / Cross valid method: THROUGHOUT / ESU R: 0.112 / ESU R Free: 0.114 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 23.173 Å2
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Refinement step | Cycle: LAST / Resolution: 1.7→83 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.7→1.744 Å / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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