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- PDB-4wki: Crystal structure of human ADAMTS-4 in complex with inhibitor 5-C... -

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Basic information

Entry
Database: PDB / ID: 4wki
TitleCrystal structure of human ADAMTS-4 in complex with inhibitor 5-CHLORO-N-{[(4S)-4-(1-METHYL-1H-IMIDAZOL-2-YL)-2,5-DIOXOIMIDAZOLIDIN-4-YL]METHYL}-1-BENZOFURAN-2-CARBOXAMIDE (compound 11)
ComponentsA disintegrin and metalloproteinase with thrombospondin motifs 4
Keywordshydrolase/hydrolase inhibitor / Metalloprotease / Osteoarthritis / Inhibitor / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


ADAMTS-4 endopeptidase / Defective B3GALTL causes PpS / O-glycosylation of TSR domain-containing proteins / extracellular matrix disassembly / Degradation of the extracellular matrix / extracellular matrix organization / extracellular matrix / skeletal system development / metalloendopeptidase activity / metallopeptidase activity ...ADAMTS-4 endopeptidase / Defective B3GALTL causes PpS / O-glycosylation of TSR domain-containing proteins / extracellular matrix disassembly / Degradation of the extracellular matrix / extracellular matrix organization / extracellular matrix / skeletal system development / metalloendopeptidase activity / metallopeptidase activity / peptidase activity / collagen-containing extracellular matrix / protease binding / nuclear speck / proteolysis / extracellular space / zinc ion binding / extracellular region
Similarity search - Function
ADAMTS/ADAMTS-like, Spacer 1 / ADAMTS/ADAMTS-like / ADAMTS, cysteine-rich domain 2 / ADAMTS/ADAMTS-like, cysteine-rich domain 3 / ADAM-TS Spacer 1 / ADAMTS cysteine-rich domain 2 / ADAMTS cysteine-rich domain / ADAM, cysteine-rich domain / ADAM Cysteine-Rich Domain / Reprolysin (M12B) family zinc metalloprotease ...ADAMTS/ADAMTS-like, Spacer 1 / ADAMTS/ADAMTS-like / ADAMTS, cysteine-rich domain 2 / ADAMTS/ADAMTS-like, cysteine-rich domain 3 / ADAM-TS Spacer 1 / ADAMTS cysteine-rich domain 2 / ADAMTS cysteine-rich domain / ADAM, cysteine-rich domain / ADAM Cysteine-Rich Domain / Reprolysin (M12B) family zinc metalloprotease / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Thrombospondin type 1 domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3PW / A disintegrin and metalloproteinase with thrombospondin motifs 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsDurbin, J.D.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.
Authors: Durham, T.B. / Klimkowski, V.J. / Rito, C.J. / Marimuthu, J. / Toth, J.L. / Liu, C. / Durbin, J.D. / Stout, S.L. / Adams, L. / Swearingen, C. / Lin, C. / Chambers, M.G. / Thirunavukkarasu, K. / Wiley, M.R.
History
DepositionOct 2, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 10, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: Database references
Revision 1.2Jan 14, 2015Group: Database references
Revision 1.3Feb 4, 2015Group: Derived calculations
Revision 1.4Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / refine_hist / struct_conn / struct_keywords
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: A disintegrin and metalloproteinase with thrombospondin motifs 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,1207
Polymers25,4851
Non-polymers6356
Water3,927218
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.037, 68.193, 74.013
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein A disintegrin and metalloproteinase with thrombospondin motifs 4 / ADAMTS-4 / ADMP-1 / Aggrecanase-1


Mass: 25484.881 Da / Num. of mol.: 1 / Fragment: unp residues 213-439
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAMTS4, KIAA0688, UNQ769/PRO1563 / Cell (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O75173, ADAMTS-4 endopeptidase

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Non-polymers , 5 types, 224 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-3PW / 5-chloro-N-{[(4S)-4-(1-methyl-1H-imidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl}-1-benzofuran-2-carboxamide


Mass: 387.777 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14ClN5O4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 1.98 Å3/Da / Density % sol: 37.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: PEG 3350, Bis-Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.98 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 11, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.52→20.08 Å / Num. obs: 31760 / % possible obs: 97.9 % / Redundancy: 6.1 % / Net I/σ(I): 6.1

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→20.07 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.943 / SU B: 2.512 / SU ML: 0.087 / Cross valid method: THROUGHOUT / ESU R: 0.103 / ESU R Free: 0.101 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2316 1019 3.7 %RANDOM
Rwork0.1985 26354 --
obs0.1998 26354 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 65.59 Å2 / Biso mean: 35.341 Å2 / Biso min: 21.63 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å20 Å2
2---1.45 Å20 Å2
3---1.45 Å2
Refinement stepCycle: final / Resolution: 1.6→20.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1618 0 35 218 1871
Biso mean--38 46.63 -
Num. residues----214
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0191739
X-RAY DIFFRACTIONr_bond_other_d0.0020.021616
X-RAY DIFFRACTIONr_angle_refined_deg1.3311.9842384
X-RAY DIFFRACTIONr_angle_other_deg0.80133734
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7325225
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.71123.61172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.21315267
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9421511
X-RAY DIFFRACTIONr_chiral_restr0.0730.2270
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211992
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02378
X-RAY DIFFRACTIONr_mcbond_it1.443.368867
X-RAY DIFFRACTIONr_mcbond_other1.443.366866
X-RAY DIFFRACTIONr_mcangle_it2.2325.0381082
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.267 72 -
Rwork0.284 1906 -
all-1978 -
obs--100 %

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