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- PDB-5d2b: Crystal structure of a mutated catalytic domain of Human MMP12 in... -

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Basic information

Entry
Database: PDB / ID: 5d2b
TitleCrystal structure of a mutated catalytic domain of Human MMP12 in complex with an hydroxamate analogue of RXP470
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / Metzincin / Matrix Metallo Elastase / MMP12 / human / RXP470 / Macrophage / Hydroxamate based inhibitor
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-56O / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsRouanet-Mehouas, C. / Devel, L. / Dive, V. / Stura, E.A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.
Authors: Rouanet-Mehouas, C. / Czarny, B. / Beau, F. / Cassar-Lajeunesse, E. / Stura, E.A. / Dive, V. / Devel, L.
History
DepositionAug 5, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Jan 11, 2017Group: Database references
Revision 1.3Jan 25, 2017Group: Database references
Revision 1.4Dec 20, 2017Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.5Jan 10, 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.ptnr2_auth_seq_id

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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)18,5257
Polymers17,6161
Non-polymers9096
Water5,278293
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-23 kcal/mol
Surface area8010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.900, 63.100, 36.790
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-421-

HOH

21A-429-

HOH

31A-476-

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 / Fragment: Catalytic domain UNP residues 106-263 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Production host: Escherichia coli BL21(DE3) (bacteria) / 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-56O / N-[(2R)-2-{[3-(3'-chlorobiphenyl-4-yl)-1,2-oxazol-5-yl]methyl}-4-(hydroxyamino)-4-oxobutanoyl]-L-alpha-glutamyl-L-alpha-glutamine


Mass: 658.056 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32ClN5O10
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 293 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: Protein : hMMP12 F171D at 820 micro-M + 10 milli-M AHA + 0.708 milli-M inhibitor. Precipitant : 20% PEG4000, 0.2 M TRIS pH 9.5 Cryoprotectant : 10 % diethylene glycol + 5 % glycerol + 10 % ...Details: Protein : hMMP12 F171D at 820 micro-M + 10 milli-M AHA + 0.708 milli-M inhibitor. Precipitant : 20% PEG4000, 0.2 M TRIS pH 9.5 Cryoprotectant : 10 % diethylene glycol + 5 % glycerol + 10 % 1,2-propanediol + 5 % 1,4-dioxane + 25% PEG6000 + 0.1 M TRIS HCl pH 8.0
PH range: 8.0-9.5 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 stream
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9184 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 22, 2015
Details: convex horizontal pre-focussing mirror (HPM) and a pair of focusing bimorph mirrors in Kirkpatrick-Baez (KB) configuration
RadiationMonochromator: cryogenically cooled channel-cut Si[111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.2→32.453 Å / Num. all: 96966 / Num. obs: 96542 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.6 % / Rmerge(I) obs: 0.1 / Rsym value: 0.089 / Net I/σ(I): 8.78
Reflection shellResolution: 1.2→1.23 Å / Redundancy: 2.9 % / Rmerge(I) obs: 1.05 / Mean I/σ(I) obs: 1.53 / % possible all: 96.9

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Processing

Software
NameVersionClassification
PHENIX1.8_1069refinement
XDSdata reduction
MOLREPphasing
MxCuBEdata collection
Cootmodel building
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQL

4gql


Resolution: 1.2→32.453 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1 / Phase error: 18.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1747 4815 4.99 %Random
Rwork0.1544 ---
obs0.1554 96507 99.53 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.2→32.453 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1246 0 51 293 1590
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051533
X-RAY DIFFRACTIONf_angle_d1.0672099
X-RAY DIFFRACTIONf_dihedral_angle_d14.719560
X-RAY DIFFRACTIONf_chiral_restr0.07206
X-RAY DIFFRACTIONf_plane_restr0.006283
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.21360.2811510.31272967X-RAY DIFFRACTION95
1.2136-1.22790.34871630.29713029X-RAY DIFFRACTION98
1.2279-1.24290.32951540.27462968X-RAY DIFFRACTION99
1.2429-1.25860.29951620.26443094X-RAY DIFFRACTION99
1.2586-1.27520.22651600.23063065X-RAY DIFFRACTION100
1.2752-1.29260.18291620.20343047X-RAY DIFFRACTION100
1.2926-1.31110.27631610.20593091X-RAY DIFFRACTION100
1.3111-1.33070.22251630.19243023X-RAY DIFFRACTION100
1.3307-1.35150.18871660.18113095X-RAY DIFFRACTION100
1.3515-1.37360.20091570.18063053X-RAY DIFFRACTION100
1.3736-1.39730.18571630.16963077X-RAY DIFFRACTION100
1.3973-1.42270.17651540.15793042X-RAY DIFFRACTION100
1.4227-1.45010.17891570.15573094X-RAY DIFFRACTION100
1.4501-1.47970.1611610.15063097X-RAY DIFFRACTION100
1.4797-1.51190.16831600.14323052X-RAY DIFFRACTION100
1.5119-1.5470.20691630.14233072X-RAY DIFFRACTION100
1.547-1.58570.1331670.14123087X-RAY DIFFRACTION100
1.5857-1.62860.18541580.13883045X-RAY DIFFRACTION100
1.6286-1.67650.14251640.13523098X-RAY DIFFRACTION100
1.6765-1.73060.16841610.14153050X-RAY DIFFRACTION100
1.7306-1.79250.15751570.14153055X-RAY DIFFRACTION100
1.7925-1.86420.1381680.13663085X-RAY DIFFRACTION100
1.8642-1.94910.14571600.13113063X-RAY DIFFRACTION100
1.9491-2.05180.15651600.13913083X-RAY DIFFRACTION100
2.0518-2.18030.17551630.13683053X-RAY DIFFRACTION100
2.1803-2.34860.18291620.14923049X-RAY DIFFRACTION100
2.3486-2.58490.17751600.15083092X-RAY DIFFRACTION100
2.5849-2.95870.16581630.15593054X-RAY DIFFRACTION100
2.9587-3.72680.17931610.13743089X-RAY DIFFRACTION100
3.7268-32.46510.14631540.14672923X-RAY DIFFRACTION96

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