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- PDB-7nxm: Structure of human cathepsin K in complex with the selective acti... -

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Basic information

Entry
Database: PDB / ID: 7nxm
TitleStructure of human cathepsin K in complex with the selective activity-based probe Gu3416
ComponentsCathepsin K
KeywordsHYDROLASE / inhibitor / complex / activity-based probe / acrylamide inhibitor
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 peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
Chem-UUW / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsBusa, M. / Benysek, J. / Lemke, C. / Gutschow, M. / Mares, M.
CitationJournal: J.Med.Chem. / Year: 2021
Title: An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity.
Authors: Lemke, C. / Benysek, J. / Brajtenbach, D. / Breuer, C. / Jilkova, A. / Horn, M. / Busa, M. / Ulrychova, L. / Illies, A. / Kubatzky, K.F. / Bartz, U. / Mares, M. / Gutschow, M.
History
DepositionMar 18, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)24,2993
Polymers23,6811
Non-polymers6192
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-8 kcal/mol
Surface area9850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.045, 71.677, 80.856
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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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 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-UUW / N-(4-(dibenzylamino)-4-oxobutyl)-2-(5-(dimethylamino)pentanamido)-4-methylpentanamide / (2~{S})-~{N}-[4-[bis(phenylmethyl)amino]-4-oxidanylidene-butyl]-2-[5-(dimethylamino)pentanoylamino]-4-methyl-pentanamide / activity-based probe Gu3416 / (2S)-N-[4-[bis(phenylmethyl)amino]-4-oxidanylidene-butyl]-2-[5-(dimethylamino)pentanoylamino]-4-methyl-pentanamide


Mass: 522.722 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H46N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.963 Å3/Da / Density % sol: 37.38 % / Description: Orthorhombic crystals
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Composition of reservoir solution was 0.1 M MES/imidazole buffer, containing: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD 0.03 M of each NPS (a mix containing sodium nitrate, ...Details: Composition of reservoir solution was 0.1 M MES/imidazole buffer, containing: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD 0.03 M of each NPS (a mix containing sodium nitrate, disodium hydrogen phosphate and ammonium sulfate) additives, pH 6.5. Morpheus C4 condition

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54187 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 5, 2020
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.72→50 Å / Num. obs: 17548 / % possible obs: 85.7 % / Redundancy: 3.8 % / CC1/2: 0.996 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.05 / Rrim(I) all: 0.079 / Χ2: 0.89 / Net I/av σ(I): 15.81 / Net I/σ(I): 27.18
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.72-1.751.30.4231.41530.6780.4230.5980.5814.8
1.8-1.842.80.2863.17720.8810.2740.3970.7674.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-3000data reduction
HKL-3000data scaling
PDB_EXTRACT3.27data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TDI

5tdi


Resolution: 1.72→35.86 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.167 / SU ML: 0.069 / Cross valid method: THROUGHOUT / ESU R: 0.137 / ESU R Free: 0.112
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.1784 895 5.111 %RANDOM
Rwork0.1602 16615 --
all0.161 ---
obs-17510 85.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 17.819 Å2
Baniso -1Baniso -2Baniso -3
1-0.356 Å2-0 Å2-0 Å2
2---1.202 Å20 Å2
3---0.846 Å2
Refinement stepCycle: LAST / Resolution: 1.72→35.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1652 0 37 184 1873
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0131776
X-RAY DIFFRACTIONr_bond_other_d0.0020.0181640
X-RAY DIFFRACTIONr_angle_refined_deg1.6331.642408
X-RAY DIFFRACTIONr_angle_other_deg1.4651.5893778
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8965231
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.74622.63295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.42315293
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg13.112151
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2251510
X-RAY DIFFRACTIONr_chiral_restr0.0850.2215
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022104
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02440
X-RAY DIFFRACTIONr_nbd_refined0.2090.2349
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1890.21535
X-RAY DIFFRACTIONr_nbtor_refined0.1750.2871
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.2775
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2130
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1410.27
X-RAY DIFFRACTIONr_nbd_other0.1670.237
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2230.27
X-RAY DIFFRACTIONr_mcbond_it1.6751.598879
X-RAY DIFFRACTIONr_mcbond_other1.6611.596878
X-RAY DIFFRACTIONr_mcangle_it2.3772.3871101
X-RAY DIFFRACTIONr_mcangle_other2.382.3891102
X-RAY DIFFRACTIONr_scbond_it2.5792.014897
X-RAY DIFFRACTIONr_scbond_other2.5782.016898
X-RAY DIFFRACTIONr_scangle_it3.852.881299
X-RAY DIFFRACTIONr_scangle_other3.8492.8821300
X-RAY DIFFRACTIONr_lrange_it5.2819.9762065
X-RAY DIFFRACTIONr_lrange_other5.1419.7452043
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.72-1.7650.409200.256272X-RAY DIFFRACTION19.6369
1.765-1.8130.241460.247771X-RAY DIFFRACTION56.9338
1.813-1.8660.267660.2031050X-RAY DIFFRACTION78.4259
1.866-1.9230.174680.1751078X-RAY DIFFRACTION84.0176
1.923-1.9860.143470.1511107X-RAY DIFFRACTION86.5716
1.986-2.0560.214670.1611113X-RAY DIFFRACTION91.2606
2.056-2.1330.137610.1451118X-RAY DIFFRACTION93.2016
2.133-2.220.16540.1361104X-RAY DIFFRACTION98.2188
2.22-2.3190.124650.1381065X-RAY DIFFRACTION96.7466
2.319-2.4320.204650.151023X-RAY DIFFRACTION99.2701
2.432-2.5630.155480.154991X-RAY DIFFRACTION97.2846
2.563-2.7190.165420.167943X-RAY DIFFRACTION97.0443
2.719-2.9060.234440.165889X-RAY DIFFRACTION98.5217
2.906-3.1390.175430.152817X-RAY DIFFRACTION98.1735
3.139-3.4380.255350.164763X-RAY DIFFRACTION98.2759
3.438-3.8430.145420.148678X-RAY DIFFRACTION94.9868
3.843-4.4350.144310.14563X-RAY DIFFRACTION89.1892
4.435-5.4280.2220.164564X-RAY DIFFRACTION100
5.428-7.6590.186180.203435X-RAY DIFFRACTION100
7.659-35.860.145110.18271X-RAY DIFFRACTION98.9474

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