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- PDB-1nl6: Crystal Structure Of The Cysteine Protease Human Cathepsin K In C... -

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Basic information

Entry
Database: PDB / ID: 1nl6
TitleCrystal Structure Of The Cysteine Protease Human Cathepsin K In Complex With A Covalent Azepanone Inhibitor
ComponentsCathepsin K
KeywordsHYDROLASE / SULFHYDRYL PROTEINASE
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-750 / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSmith, W.W. / Janson, C.A. / Zhao, B.
CitationJournal: J.Med.Chem. / Year: 2001
Title: Azepanone-based inhibitors of human and rat cathepsin K
Authors: Marquis, R.W. / Ru, Y. / LoCastro, S.M. / Zeng, J. / Yamashita, D.S. / Oh, H.J. / Erhard, K.F. / Davis, L.D. / Tomaszek, T.A. / Tew, D. / Salyers, K. / Proksch, J. / Ward, K. / Smith, B. / ...Authors: Marquis, R.W. / Ru, Y. / LoCastro, S.M. / Zeng, J. / Yamashita, D.S. / Oh, H.J. / Erhard, K.F. / Davis, L.D. / Tomaszek, T.A. / Tew, D. / Salyers, K. / Proksch, J. / Ward, K. / Smith, B. / Levy, M. / Cummings, M.D. / Haltiwanger, R.C. / Trescher, G. / Wang, B. / Hemling, M.E. / Quinn, C.J. / Cheng, H.-Y. / Lin, F. / Smith, W.W. / Janson, C.A. / Zhao, B. / McQueney, M.S. / D'Alessio, K. / Lee, C.P. / Marzulli, A. / A Dodds, R. / Blake, S. / Hwang, S.M. / James, I.E. / Gress, C.J. / Bradley, B.R. / Lark, M.W. / Gowen, M. / Veber, D.F.
History
DepositionJan 6, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software
Revision 1.4Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)48,4674
Polymers47,0472
Non-polymers1,4202
Water00
1
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2332
Polymers23,5231
Non-polymers7101
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2332
Polymers23,5231
Non-polymers7101
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.816, 75.888, 114.841
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 X / Cathepsin O2


Mass: 23523.480 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-750 / 5-(2-MORPHOLIN-4-YLETHOXY)BENZOFURAN-2-CARBOXYLIC ACID ((S)-3-METHYL-1-{(S)-3-OXO-1-[2-(3-PYRIDIN-2-YLPHENYL)ACETYL]AZEPAN-4-YLCARBAMOYL}BUTYL)AMIDE


Mass: 709.830 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C40H47N5O7

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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: 3.32 Å3/Da / Density % sol: 63 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 10% PEG 8000, 0.1 M imidazole, 0.2 M calcium acetate, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 298K
Crystal grow
*PLUS
Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
110 %PEG80001reservoir
20.1 Mimidazole1reservoirpH8.0
30.2 Mcadmium acetate1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Mar 1, 2000
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→99 Å / Num. all: 19740 / Num. obs: 17372 / % possible obs: 88 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 9.8 % / Rmerge(I) obs: 0.58 / Rsym value: 0.58 / Net I/σ(I): 32
Reflection shellResolution: 2.55→2.59 Å / Rmerge(I) obs: 0.94 / Mean I/σ(I) obs: 9.9 / Num. unique all: 631 / Rsym value: 0.94 / % possible all: 65
Reflection
*PLUS
Lowest resolution: 99 Å / % possible obs: 88 %

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Processing

Software
NameClassification
MAR345data collection
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1ATK

1atk


Resolution: 2.8→6 Å / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2979 1578 10 %RANDOM
Rwork0.2461 ---
all0.25 16025 --
obs0.2461 15561 97 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--21.858 Å20 Å20 Å2
2--13.558 Å20 Å2
3---8.3 Å2
Refinement stepCycle: LAST / Resolution: 2.8→6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3298 0 104 0 3402
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.39
LS refinement shellResolution: 2.8→2.83 Å
RfactorNum. reflection% reflection
Rfree0.368 22 13 %
Rwork0.324 160 -
obs-14141 95 %
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2sb331750.param
Refinement
*PLUS
Lowest resolution: 6 Å / % reflection Rfree: 10 % / Rfactor Rwork: 0.26
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Type: c_bond_d / Dev ideal: 0.01

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