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- PDB-6yjm: Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex ... -

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Basic information

Entry
Database: PDB / ID: 6yjm
TitleCrystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with the Inhibitor GLPG1972
ComponentsA disintegrin and metalloproteinase with thrombospondin motifs 5
KeywordsHYDROLASE / zinc metalloproteinase / aggrecanase
Function / homology
Function and homology information


Defective B3GALTL causes PpS / O-glycosylation of TSR domain-containing proteins / pulmonary valve morphogenesis / myoblast fusion / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / extracellular matrix binding / aortic valve morphogenesis / negative regulation of cold-induced thermogenesis / endocardial cushion morphogenesis / extracellular matrix disassembly ...Defective B3GALTL causes PpS / O-glycosylation of TSR domain-containing proteins / pulmonary valve morphogenesis / myoblast fusion / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / extracellular matrix binding / aortic valve morphogenesis / negative regulation of cold-induced thermogenesis / endocardial cushion morphogenesis / extracellular matrix disassembly / Degradation of the extracellular matrix / extracellular matrix / extracellular matrix organization / metalloendopeptidase activity / integrin binding / metallopeptidase activity / heparin binding / peptidase activity / endopeptidase activity / collagen-containing extracellular matrix / defense response to bacterium / endoplasmic reticulum lumen / proteolysis / extracellular space / zinc ion binding / extracellular region / identical protein binding
Similarity search - Function
Peptidase M12B, ADAM-TS5 / Thrombospondin type 1 domain / 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 ...Peptidase M12B, ADAM-TS5 / Thrombospondin type 1 domain / 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 / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-OU5 / A disintegrin and metalloproteinase with thrombospondin motifs 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsGoepfert, A. / Leonard, P. / Triballeau, N. / Fleury, D. / Mollat, P. / Lamers, M.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis.
Authors: Brebion, F. / Gosmini, R. / Deprez, P. / Varin, M. / Peixoto, C. / Alvey, L. / Jary, H. / Bienvenu, N. / Triballeau, N. / Blanque, R. / Cottereaux, C. / Christophe, T. / Vandervoort, N. / ...Authors: Brebion, F. / Gosmini, R. / Deprez, P. / Varin, M. / Peixoto, C. / Alvey, L. / Jary, H. / Bienvenu, N. / Triballeau, N. / Blanque, R. / Cottereaux, C. / Christophe, T. / Vandervoort, N. / Mollat, P. / Touitou, R. / Leonard, P. / De Ceuninck, F. / Botez, I. / Monjardet, A. / van der Aar, E. / Amantini, D.
History
DepositionApr 3, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 24, 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

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Assembly

Deposited unit
A: A disintegrin and metalloproteinase with thrombospondin motifs 5
B: A disintegrin and metalloproteinase with thrombospondin motifs 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,58612
Polymers49,4022
Non-polymers1,18410
Water1,69394
1
A: A disintegrin and metalloproteinase with thrombospondin motifs 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2936
Polymers24,7011
Non-polymers5925
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: A disintegrin and metalloproteinase with thrombospondin motifs 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2936
Polymers24,7011
Non-polymers5925
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.320, 80.240, 51.050
Angle α, β, γ (deg.)90.00, 90.20, 90.00
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein A disintegrin and metalloproteinase with thrombospondin motifs 5 / ADAMTS-5 / A disintegrin and metalloproteinase with thrombospondin motifs 11 / ADAMTS-11 / ADMP-2 / ...ADAMTS-5 / A disintegrin and metalloproteinase with thrombospondin motifs 11 / ADAMTS-11 / ADMP-2 / Aggrecanase-2


Mass: 24700.969 Da / Num. of mol.: 2 / Mutation: L282K
Source method: isolated from a genetically manipulated source
Details: The three last amino acids of the sequence (VPR) are part of an engineered Thrombin enzyme cleavage site.
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAMTS5, ADAMTS11, ADMP2 / Production host: Homo sapiens (human)
References: UniProt: Q9UNA0, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Zn
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-OU5 / (5~{S})-5-[3-[(3~{S})-4-[3,5-bis(fluoranyl)phenyl]-3-methyl-piperazin-1-yl]-3-oxidanylidene-propyl]-5-cyclopropyl-imidazolidine-2,4-dione


Mass: 406.426 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C20H24F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 1.89 Å3/Da / Density % sol: 34.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1M HEPES pH 7.0, 300% v/v Jeffamine ED-2001 pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Nov 28, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.25→18.5 Å / Num. obs: 15333 / % possible obs: 86.24 % / Redundancy: 5 % / Biso Wilson estimate: 16.796483553 Å2 / CC1/2: 0.948 / CC star: 0.986 / Net I/σ(I): 19.05
Reflection shellResolution: 2.25→2.33 Å / Mean I/σ(I) obs: 5.4 / Num. unique obs: 877 / CC1/2: 0.671 / CC star: 0.896 / % possible all: 51.02

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LJT

3ljt


Resolution: 2.25→18.47 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.862 / SU B: 0.005 / SU ML: 0 / Cross valid method: THROUGHOUT / ESU R: 0.253 / ESU R Free: 0.305 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25563 737 5 %RANDOM
Rwork0.2125 ---
obs0.21466 13962 86.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.366 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2--0 Å20 Å2
3---0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.25→18.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3275 0 66 94 3435
LS refinement shellResolution: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 36 -
Rwork0.236 558 -
obs--48.21 %

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