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- PDB-2r6n: Crystal structure of a pyrrolopyrimidine inhibitor in complex wit... -

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Basic information

Entry
Database: PDB / ID: 2r6n
TitleCrystal structure of a pyrrolopyrimidine inhibitor in complex with human Cathepsin K
ComponentsCathepsin K
KeywordsHYDROLASE / covalent bond to inhibitor / Disease mutation / Glycoprotein / Lysosome / Protease / Thiol protease / Zymogen
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-CKE / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
AuthorsCowan-Jacob, S.W. / Ramage, P. / Mathis, B. / Geisse, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Novel scaffold for cathepsin K inhibitors.
Authors: Teno, N. / Miyake, T. / Ehara, T. / Irie, O. / Sakaki, J. / Ohmori, O. / Gunji, H. / Matsuura, N. / Masuya, K. / Hitomi, Y. / Nonomura, K. / Horiuchi, M. / Gohda, K. / Iwasaki, A. / Umemura, ...Authors: Teno, N. / Miyake, T. / Ehara, T. / Irie, O. / Sakaki, J. / Ohmori, O. / Gunji, H. / Matsuura, N. / Masuya, K. / Hitomi, Y. / Nonomura, K. / Horiuchi, M. / Gohda, K. / Iwasaki, A. / Umemura, I. / Tada, S. / Kometani, M. / Iwasaki, G. / Cowan-Jacob, S.W. / Missbach, M. / Lattmann, R. / Betschart, C.
History
DepositionSep 6, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.classification / _software.name
Remark 600heterogen The ligand CKE is covalently bonded to Cys25 of chain A through atom C09, and the bond ...heterogen The ligand CKE is covalently bonded to Cys25 of chain A through atom C09, and the bond between C09 and N10 is a single bond. The pro-ligand before convalently linking to protein has triple bond between C09 and N10, which is indicated as compound 5e in the primary citation of the structure.

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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)24,1562
Polymers23,7381
Non-polymers4191
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.400, 62.400, 121.800
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

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


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: PMBAC-HC9 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF21 / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-CKE / 1-{7-cyclohexyl-6-[4-(4-methylpiperazin-1-yl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}methanamine


Mass: 418.578 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 143 / Source method: isolated from a natural source / Formula: H2O

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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: 2.88 Å3/Da / Density % sol: 57.35 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 20 % PEG 4000, 10 % Isopropanol, 0.1 M HEPES pH 7.5, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Aug 1, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. all: 19305 / Num. obs: 19305 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.8 % / Rmerge(I) obs: 0.0563 / Net I/σ(I): 43.4
Reflection shellResolution: 1.95→2 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.145 / Mean I/σ(I) obs: 11 / % possible all: 96.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
AMoREphasing
CNSrefinement
PDB_EXTRACT3data extraction
MAR345dtbdata collection
XDSdata reduction
AUTOMARdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→20 Å / FOM work R set: 0.9 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflection
Rfree0.184 910 4.7 %
Rwork0.156 --
all-19305 -
obs-19162 98.1 %
Displacement parametersBiso mean: 21.255 Å2
Baniso -1Baniso -2Baniso -3
1--0.805 Å2-3.472 Å20 Å2
2---0.805 Å20 Å2
3---1.611 Å2
Refinement stepCycle: LAST / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1732 0 31 143 1906
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_d1.172
X-RAY DIFFRACTIONc_mcbond_it1.1671.5
X-RAY DIFFRACTIONc_scbond_it1.9832
X-RAY DIFFRACTIONc_mcangle_it1.7542
X-RAY DIFFRACTIONc_scangle_it3.1162.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:dna-rna_rep.paramMSI_CNX_TOPPAR:dna-rna.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5inh2.parinh2.top

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