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- PDB-6qlw: Cathepsin-K in complex with MIV-710 -

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Basic information

Entry
Database: PDB / ID: 6qlw
TitleCathepsin-K in complex with MIV-710
ComponentsCathepsin K
KeywordsHYDROLASE / inhibitor complex / lysosomal cysteine 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 / endolysosome lumen / thyroid hormone generation / 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 / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / cysteine-type endopeptidase activator activity involved in apoptotic process / Collagen degradation / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / bone resorption / mitophagy / cellular response to transforming growth factor beta stimulus / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / response to insulin / positive regulation of apoptotic signaling pathway / : / 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 peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cysteine proteinases / Cathepsin B; Chain A / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-J5T / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsDerbyshire, D.J.
CitationJournal: To Be Published
Title: Successful development of 3-oxohexahydrofuropyrrole amino acid amides as inhibitors of Cathepsin-K.
Authors: Derbyshire, D.J.
History
DepositionFeb 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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
C: Cathepsin K
D: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,33717
Polymers94,7234
Non-polymers2,61513
Water16,195899
1
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3906
Polymers23,6811
Non-polymers7095
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2963
Polymers23,6811
Non-polymers6162
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3555
Polymers23,6811
Non-polymers6744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2963
Polymers23,6811
Non-polymers6162
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.727, 69.484, 78.680
Angle α, β, γ (deg.)90.000, 100.890, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 23680.674 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Plasmid: pET16b / Production host: Escherichia coli (E. coli) / References: UniProt: P43235, cathepsin K
#2: Chemical
ChemComp-J5T / ~{N}-[(2~{S})-1-[(3~{R},3~{a}~{R},6~{R},6~{a}~{S})-6-chloranyl-3-oxidanyl-2,3,3~{a},5,6,6~{a}-hexahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxidanylidene-pentan-2-yl]-4-[5-fluoranyl-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide


Mass: 580.114 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H35ClFN5O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 899 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.15 Å3/Da / Density % sol: 42.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.1
Details: 25mM ADA pH6.1, 250mM sodium nitrate and 20% PEG 5k.mme
PH range: 6.0 - 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 25, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2→74.473 Å / Num. obs: 52114 / % possible obs: 96 % / Redundancy: 3.3 % / CC1/2: 0.98 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.091 / Rrim(I) all: 0.175 / Net I/σ(I): 7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2-2.052.10.59631420.5540.4750.76775.4
8.72-74.4733.90.0746950.9880.0420.08699.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.3 Å74.36 Å
Translation3.3 Å74.36 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimless0.6.2data scaling
PHASER2.8.2phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→74.473 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.912 / SU B: 11.946 / SU ML: 0.142 / SU R Cruickshank DPI: 0.2385 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.239 / ESU R Free: 0.183
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2252 2517 4.8 %RANDOM
Rwork0.1798 ---
obs0.182 49585 95.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 58.24 Å2 / Biso mean: 21.152 Å2 / Biso min: 9.7 Å2
Baniso -1Baniso -2Baniso -3
1-2.74 Å20 Å21.43 Å2
2---1.22 Å20 Å2
3----1.93 Å2
Refinement stepCycle: final / Resolution: 2→74.473 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6626 0 165 899 7690
Biso mean--18.05 32.07 -
Num. residues----864
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0146998
X-RAY DIFFRACTIONr_bond_other_d0.0010.0186093
X-RAY DIFFRACTIONr_angle_refined_deg1.711.6889474
X-RAY DIFFRACTIONr_angle_other_deg1.0831.68114338
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4795874
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.64623.793348
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.379151148
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6371530
X-RAY DIFFRACTIONr_chiral_restr0.0860.2850
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.028006
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021310
LS refinement shellResolution: 2→2.052 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 129 -
Rwork0.257 2844 -
all-2973 -
obs--73.96 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.58260.1645-0.06370.74-0.08030.4880.0182-0.004-0.01180.03930.0158-0.0077-0.03830.0469-0.03410.09350.0045-0.05710.1603-0.00450.10721.55135.722231.5466
21.12350.40610.0461.02290.03310.5824-0.00310.02980.03320.02580.01130.0065-0.0159-0.0405-0.00810.10050.0132-0.06450.18660.00070.117942.3163.44329.4068
30.3962-0.09820.18050.6625-0.21410.7352-0.02180.00570.008-0.04090.0143-0.00610.01440.03320.00750.0929-0.0081-0.0540.1637-0.00590.11625.7045-19.81469.7907
41.05880.34530.41111.1280.33690.60360.00340.0211-0.0090.0358-0.0187-0.01240.02850.02860.01530.08640.0114-0.05310.18220.01740.130427.410117.0971.0052
50.10340.0089-0.02310.039-0.04670.0609-0.0082-0.0003-0.00240.00340.0027-0.0011-0.00610.01270.00560.03590.0034-0.05970.0916-0.00710.102618.186-0.047618.547
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 215
2X-RAY DIFFRACTION1A301
3X-RAY DIFFRACTION2B0 - 215
4X-RAY DIFFRACTION2B301
5X-RAY DIFFRACTION3C0 - 215
6X-RAY DIFFRACTION3C301
7X-RAY DIFFRACTION4D0 - 215
8X-RAY DIFFRACTION4D301
9X-RAY DIFFRACTION5W1 - 999
10X-RAY DIFFRACTION5X1 - 999

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