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- PDB-6eox: Crystal structure of MMP12 in complex with carboxylic inhibitor LP165. -

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Basic information

Entry
Database: PDB / ID: 6eox
TitleCrystal structure of MMP12 in complex with carboxylic inhibitor LP165.
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / metzincin / carboxylate inhibitor alternative zinc-binding groups
Function / homology
Function and homology information


macrophage elastase / negative regulation of endothelial cell-matrix adhesion / 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 / 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 / positive regulation of interferon-alpha production / extracellular matrix disassembly / 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 / extracellular region / zinc ion binding / nucleus / cytoplasm
Similarity search - Function
Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidoglycan binding-like / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Putative peptidoglycan binding domain ...Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidoglycan binding-like / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Putative peptidoglycan binding domain / Hemopexin repeat profile. / Hemopexin-like repeats. / Peptidase M10A / Peptidase M10A, catalytic domain / Peptidase M10, metallopeptidase / Matrixin / PGBD-like superfamily / Peptidase, metallopeptidase / Zinc-dependent metalloprotease / 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-BKW / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsVera, L. / Nuti, E. / Rossello, A. / Stura, E.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.
Authors: Nuti, E. / Cuffaro, D. / Bernardini, E. / Camodeca, C. / Panelli, L. / Chaves, S. / Ciccone, L. / Tepshi, L. / Vera, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Santos, M.A. / Dive, V. / Rossello, A.
History
DepositionOct 10, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2497
Polymers17,6161
Non-polymers6336
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-23 kcal/mol
Surface area8010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.160, 59.860, 53.940
Angle α, β, γ (deg.)90.00, 115.73, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-461-

HOH

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Components

#1: Protein Macrophage metalloelastase / MME / Macrophage elastase / hME / Matrix metalloproteinase-12 / MMP-12


Mass: 17615.670 Da / Num. of mol.: 1 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Details: Fragment: MMP-12 catalytic sub-unit (RESIDUES 106-263)
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli (E. coli) / References: UniProt: P39900, macrophage elastase
#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-BKW / 2-[2-[4-(4-methoxyphenyl)phenyl]sulfonylphenyl]ethanoic acid


Mass: 382.430 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18O5S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 2.11 Å3/Da / Density % sol: 41.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Drop: 1 micro-L (hMMP-12 at 855 micro-M + 1 milli-M hydroxamic acid + 1 milli-M LP165) and 1 micro-L reservoir solution. Precipitant: 17% PEG 20K, 0.2M imidazole malate 250mM NaCl, pH 8.5. ...Details: Drop: 1 micro-L (hMMP-12 at 855 micro-M + 1 milli-M hydroxamic acid + 1 milli-M LP165) and 1 micro-L reservoir solution. Precipitant: 17% PEG 20K, 0.2M imidazole malate 250mM NaCl, pH 8.5. Cryoprotection: 40% MPEG 5K, 10% 1,2-propanediol, 10% AAB (sodium acetate, ADA, bicine: 90% basic/10% acid), pH 8.0
PH range: 8-8.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryostream
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM30A / Wavelength: 0.979696 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 25, 2010 / Details: 2nd mirror Zerodur with Pt coating
RadiationMonochromator: double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979696 Å / Relative weight: 1
ReflectionResolution: 1.3→49 Å / Num. obs: 28894 / % possible obs: 79.7 % / Observed criterion σ(I): -3 / Redundancy: 4.14 % / CC1/2: 0.999 / Net I/σ(I): 14.42
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 3.68 % / Mean I/σ(I) obs: 1.02 / CC1/2: 0.343 / Rsym value: 1.31 / % possible all: 31.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H76

4h76


Resolution: 1.3→48.59 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.968 / SU B: 2.886 / SU ML: 0.049 / Cross valid method: THROUGHOUT / ESU R: 0.072 / ESU R Free: 0.062 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.179 1996 6.9 %RANDOM
Rwork0.142 ---
obs0.145 26772 79.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 18.43 Å2
Baniso -1Baniso -2Baniso -3
1-0.4 Å20 Å2-0.06 Å2
2---0.39 Å20 Å2
3---0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.3→48.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1238 0 32 197 1467
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0720.0191448
X-RAY DIFFRACTIONr_bond_other_d0.0020.021259
X-RAY DIFFRACTIONr_angle_refined_deg1.6491.9471950
X-RAY DIFFRACTIONr_angle_other_deg1.93632905
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7755177
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.8622.25471
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.30215219
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7521513
X-RAY DIFFRACTIONr_chiral_restr0.1130.2191
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021668
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02349
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_it2.1471.542692
X-RAY DIFFRACTIONr_mcbond_other2.1351.539691
X-RAY DIFFRACTIONr_mcangle_it2.4812.33869
X-RAY DIFFRACTIONr_mcangle_other2.4812.332870
X-RAY DIFFRACTIONr_scbond_it2.91.819754
X-RAY DIFFRACTIONr_scbond_other2.8991.82755
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.3122.6251081
X-RAY DIFFRACTIONr_long_range_B_refined3.85420.5791753
X-RAY DIFFRACTIONr_long_range_B_other3.59719.7891704
X-RAY DIFFRACTIONr_rigid_bond_restr6.9832695
X-RAY DIFFRACTIONr_sphericity_free21.9235119
X-RAY DIFFRACTIONr_sphericity_bonded7.58352711
LS refinement shellResolution: 1.3→1.33 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.413 44 -
Rwork0.396 656 -
obs--26.56 %

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