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- PDB-6ela: Crystal structure of MMP12 in complex with inhibitor BE4. -

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Basic information

Entry
Database: PDB / ID: 6ela
TitleCrystal structure of MMP12 in complex with inhibitor BE4.
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 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 / positive regulation of interferon-alpha production / collagen catabolic process / 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-B9Z / 1,4-DIETHYLENE DIOXIDE / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.485 Å
AuthorsCiccone, L. / Tepshi, 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
DepositionSep 28, 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 ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _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.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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
B: Macrophage metalloelastase
C: Macrophage metalloelastase
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,42734
Polymers70,2304
Non-polymers3,19730
Water15,547863
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3198
Polymers17,5581
Non-polymers7627
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3198
Polymers17,5581
Non-polymers7627
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3819
Polymers17,5581
Non-polymers8248
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4079
Polymers17,5581
Non-polymers8508
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.190, 63.320, 78.320
Angle α, β, γ (deg.)90.00, 103.73, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 17557.568 Da / Num. of mol.: 4 / Mutation: F171D, K241A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli (E. coli) / References: UniProt: P39900, macrophage elastase

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Non-polymers , 6 types, 893 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-B9Z / (2~{S})-2-[2-[4-(4-methoxyphenyl)phenyl]sulfanylphenyl]pentanedioic acid


Mass: 422.493 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H22O5S
#5: Chemical
ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H8O2
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 863 / 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: 2.2 Å3/Da / Density % sol: 44.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: protein solution: hMMP12 at 314 micro-M + 10 milli-M acetohydroxamate + 1 milli-M BE4, 10% DMSO precipitant: 38% PEG 4K, 0.16 M imidazole piperidine,15% Dioxane, pH 8.5. Cryoprotectant: 40% ...Details: protein solution: hMMP12 at 314 micro-M + 10 milli-M acetohydroxamate + 1 milli-M BE4, 10% DMSO precipitant: 38% PEG 4K, 0.16 M imidazole piperidine,15% Dioxane, pH 8.5. Cryoprotectant: 40% CM15 (12.5 % diethylene glycol + 12.5 % ethylene glycol + 12.5 % MPD + 12.5 % glycerol + 12.5 % 1,2-propanediol + 12.5 % 1,4-dioxane + 12.5 mM NDSB 201), 25% PEG 6K, 100 milli-M TRIS HCl, pH 7.0
PH range: 7-8.5 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryostream
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.976254 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 30, 2016 / Details: microfocus
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.48→43.44 Å / Num. obs: 100074 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.67 % / CC1/2: 0.997 / Rrim(I) all: 0.137 / Rsym value: 0.127 / Net I/σ(I): 7.85
Reflection shellResolution: 1.48→1.57 Å / Redundancy: 6.51 % / Mean I/σ(I) obs: 1.68 / Num. unique obs: 15656 / CC1/2: 0.874 / Rrim(I) all: 0.85 / Rsym value: 0.78 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I4O

5i4o


Resolution: 1.485→38.041 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.01 / Phase error: 26.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2067 9797 5 %
Rwork0.1714 --
obs0.1732 195903 99.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.485→38.041 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4932 0 174 863 5969
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055493
X-RAY DIFFRACTIONf_angle_d0.7957473
X-RAY DIFFRACTIONf_dihedral_angle_d21.5791921
X-RAY DIFFRACTIONf_chiral_restr0.079743
X-RAY DIFFRACTIONf_plane_restr0.006989
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4851-1.5020.39562620.3435004X-RAY DIFFRACTION79
1.502-1.51960.34563240.32526147X-RAY DIFFRACTION100
1.5196-1.53820.31933330.30796271X-RAY DIFFRACTION100
1.5382-1.55760.39263320.3136243X-RAY DIFFRACTION100
1.5576-1.57810.32013290.28666255X-RAY DIFFRACTION100
1.5781-1.59970.31413280.25576235X-RAY DIFFRACTION100
1.5997-1.62260.26953280.25126244X-RAY DIFFRACTION100
1.6226-1.64680.30043270.24786262X-RAY DIFFRACTION100
1.6468-1.67260.27623250.23896257X-RAY DIFFRACTION100
1.6726-1.70.26113300.22446266X-RAY DIFFRACTION100
1.7-1.72930.25543290.20126173X-RAY DIFFRACTION100
1.7293-1.76070.24983290.18896273X-RAY DIFFRACTION100
1.7607-1.79460.2223270.18486271X-RAY DIFFRACTION100
1.7946-1.83120.23723280.18126219X-RAY DIFFRACTION100
1.8312-1.8710.20933300.17436280X-RAY DIFFRACTION100
1.871-1.91460.22483310.15756244X-RAY DIFFRACTION100
1.9146-1.96250.19853300.14666287X-RAY DIFFRACTION100
1.9625-2.01550.20253270.14086269X-RAY DIFFRACTION100
2.0155-2.07480.18513270.12966189X-RAY DIFFRACTION100
2.0748-2.14180.15273360.1356302X-RAY DIFFRACTION100
2.1418-2.21830.17053250.13296247X-RAY DIFFRACTION100
2.2183-2.30710.18473270.13596248X-RAY DIFFRACTION100
2.3071-2.41210.19153270.1396228X-RAY DIFFRACTION100
2.4121-2.53930.18693370.14216293X-RAY DIFFRACTION100
2.5393-2.69830.1883270.15066226X-RAY DIFFRACTION100
2.6983-2.90660.19443300.15776284X-RAY DIFFRACTION100
2.9066-3.19890.18683300.16116238X-RAY DIFFRACTION100
3.1989-3.66150.15153300.14826226X-RAY DIFFRACTION100
3.6615-4.61180.16433300.15026289X-RAY DIFFRACTION100
4.6118-38.05350.22923220.19726136X-RAY DIFFRACTION98

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