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- PDB-8rij: Discovery of the first orally bioavailable ADAMTS7 inhibitor BAY-9835 -

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Basic information

Entry
Database: PDB / ID: 8rij
TitleDiscovery of the first orally bioavailable ADAMTS7 inhibitor BAY-9835
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / MATRIX METALLOPROTEINASE / MMP12 / METALLO ELASTASE / EXTRACELLULAR MATRIX / METAL-BINDING / METALLOPROTEASE
Function / homology
Function and homology information


macrophage elastase / negative regulation of endothelial cell-matrix adhesion via fibronectin / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development ...macrophage elastase / negative regulation of endothelial cell-matrix adhesion via fibronectin / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development / response to amyloid-beta / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / positive regulation of interferon-alpha production / core promoter sequence-specific DNA binding / collagen binding / Degradation of the extracellular matrix / extracellular matrix organization / extracellular matrix / metalloendopeptidase activity / cellular response to virus / protein import into nucleus / endopeptidase activity / sequence-specific DNA binding / serine-type endopeptidase activity / calcium ion binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / proteolysis / extracellular space / zinc ion binding / extracellular region / nucleus / cytoplasm
Similarity search - Function
Peptidoglycan binding-like / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Putative peptidoglycan binding domain / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin ...Peptidoglycan binding-like / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Putative peptidoglycan binding domain / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Hemopexin repeat profile. / Hemopexin-like repeats. / Peptidase M10A / Peptidase M10A, catalytic domain / Peptidase M10, metallopeptidase / Matrixin / PGBD-like superfamily / Peptidase, metallopeptidase / Zinc-dependent metalloprotease / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
: / DI(HYDROXYETHYL)ETHER / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsSchafer, M. / Meibom, D. / Wasnaire, P. / Beyer, K. / Broehl, A. / Cancho-Grande, Y. / Elowe, N. / Henninger, K. / Johannes, S. / Jungmann, N. ...Schafer, M. / Meibom, D. / Wasnaire, P. / Beyer, K. / Broehl, A. / Cancho-Grande, Y. / Elowe, N. / Henninger, K. / Johannes, S. / Jungmann, N. / Krainz, T. / Lindner, N. / Maassen, S. / MacDonald, B. / Menshykau, D. / Mittendorf, J. / Sanchez, G. / Stefan, E. / Torge, A. / Xing, Y. / Zubov, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.
Authors: Meibom, D. / Wasnaire, P. / Beyer, K. / Broehl, A. / Cancho-Grande, Y. / Elowe, N. / Henninger, K. / Johannes, S. / Jungmann, N. / Krainz, T. / Lindner, N. / Maassen, S. / MacDonald, B. / ...Authors: Meibom, D. / Wasnaire, P. / Beyer, K. / Broehl, A. / Cancho-Grande, Y. / Elowe, N. / Henninger, K. / Johannes, S. / Jungmann, N. / Krainz, T. / Lindner, N. / Maassen, S. / MacDonald, B. / Menshykau, D. / Mittendorf, J. / Sanchez, G. / Schaefer, M. / Stefan, E. / Torge, A. / Xing, Y. / Zubov, D.
History
DepositionDec 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2359
Polymers17,4841
Non-polymers7518
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area630 Å2
ΔGint-30 kcal/mol
Surface area8050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.245, 62.986, 59.477
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 Macrophage metalloelastase / MME / Macrophage elastase / hME / Matrix metalloproteinase-12 / MMP-12


Mass: 17484.475 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Production host: Escherichia coli (E. coli) / References: UniProt: P39900, macrophage elastase

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Non-polymers , 6 types, 134 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / 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-A1H07 / ~{N}-[[(4~{R})-4-cyclopropyl-2,5-bis(oxidanylidene)imidazolidin-4-yl]methyl]-2-(3-fluorophenyl)-1,2,3-triazole-4-carboxamide


Mass: 358.327 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15FN6O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.37 Å3/Da / Density % sol: 48.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: not known

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.96→43.24 Å / Num. obs: 12419 / % possible obs: 99.7 % / Redundancy: 4.48 % / CC1/2: 0.997 / Rmerge(I) obs: 0.086 / Rrim(I) all: 0.098 / Net I/σ(I): 12.59
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.96-2.210.44537010.8970.5051
2.21-2.440.23921650.9530.2711
2.44-2.80.13221730.9860.1491
2.8-3.410.06619230.9960.0751
3.41-4.320.04412160.9970.051
4.32-5.560.0386410.9980.0431
5.56-8.110.0383950.9970.0441
8.11-12.980.0311500.9990.0361
12.98-43.240.028550.9990.0331

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.96→43.24 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.937 / SU B: 6.662 / SU ML: 0.11 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.157 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21904 1239 10 %RANDOM
Rwork0.17279 ---
obs0.17736 11180 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.522 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å2-0 Å2
2---0.23 Å20 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 1.96→43.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1238 0 39 126 1403
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0191304
X-RAY DIFFRACTIONr_bond_other_d0.0060.021144
X-RAY DIFFRACTIONr_angle_refined_deg1.5051.9491773
X-RAY DIFFRACTIONr_angle_other_deg1.32732623
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9255157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.89123.60761
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.36615180
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7155
X-RAY DIFFRACTIONr_chiral_restr0.0930.2180
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021505
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02324
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.882.147630
X-RAY DIFFRACTIONr_mcbond_other1.8462.14629
X-RAY DIFFRACTIONr_mcangle_it2.6243.611786
X-RAY DIFFRACTIONr_mcangle_other2.6283.615787
X-RAY DIFFRACTIONr_scbond_it3.1332.563674
X-RAY DIFFRACTIONr_scbond_other3.132.564674
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.2394.153985
X-RAY DIFFRACTIONr_long_range_B_refined5.73921.0481501
X-RAY DIFFRACTIONr_long_range_B_other5.67520.4031470
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.96→2.011 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 116 -
Rwork0.247 810 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -9.442 Å / Origin y: 13.596 Å / Origin z: 12.727 Å
111213212223313233
T0.0986 Å20.016 Å20.0133 Å2-0.0671 Å2-0.0127 Å2--0.0256 Å2
L1.795 °20.52 °20.3277 °2-2.7219 °20.1252 °2--2.0634 °2
S0.0258 Å °-0.2867 Å °0.1315 Å °0.2303 Å °-0.0138 Å °0.2324 Å °-0.0592 Å °-0.2447 Å °-0.012 Å °

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