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- PDB-5d3c: Crystal structure of a double mutant catalytic domain of Human MM... -

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Basic information

Entry
Database: PDB / ID: 5d3c
TitleCrystal structure of a double mutant catalytic domain of Human MMP12 in complex with an hydroxamate analogue of RXP470
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / MMP12 / Human / Macrophage MetalloElastase / RXP470 / hydroxamate
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 / positive regulation of interferon-alpha production / response to amyloid-beta / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / core promoter sequence-specific DNA binding / collagen binding / extracellular matrix / Degradation of the extracellular matrix / extracellular matrix organization / 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 / 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: 1.314 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 6, 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 1.4Jan 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 / diffrn_radiation_wavelength / 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)18,4677
Polymers17,5581
Non-polymers9096
Water4,936274
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-23 kcal/mol
Surface area7990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.640, 63.060, 36.540
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-422-

HOH

21A-467-

HOH

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Components

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


Mass: 17557.568 Da / Num. of mol.: 1 / Fragment: UNP residues 106-263 / Mutation: F171D K241A
Source method: isolated from a genetically manipulated source
Details: MMP12 F171D K141A mutant for calorimetric studies Catalytic domain (UNP residues 106-263)
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Plasmid: PET24A / 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 / Water


Mass: 18.015 Da / Num. of mol.: 274 / 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: 2.25 Å3/Da / Density % sol: 45.38 % / Description: long prismatic crystal
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: Protein : MMP12 F67D K241A, 1 mili-M + 10 mili-M AHA Drop : 1 micro-L protein + 0.2 micro-L inhibitor (5 mili-M in DMSO) Precipitant : 20% PEG4000, 0.2 M TRIS pH 9.5 Cryoprotectant : 10 % ...Details: Protein : MMP12 F67D K241A, 1 mili-M + 10 mili-M AHA Drop : 1 micro-L protein + 0.2 micro-L inhibitor (5 mili-M in DMSO) Precipitant : 20% PEG4000, 0.2 M TRIS pH 9.5 Cryoprotectant : 10 % diethylene glycol + 5 % glycerol + 10 % 2,3-butanediol + 5 % 1,4-dioxane +25% PEG6000,+ 100 mili-M TRIS HCl, pH 8.
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: 0.9801 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: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.31→46.438 Å / Num. all: 72969 / Num. obs: 71186 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.83 % / Rmerge(I) obs: 0.123 / Rsym value: 0.121 / Net I/σ(I): 9.47
Reflection shellResolution: 1.31→1.35 Å / Redundancy: 3.93 % / Rmerge(I) obs: 1.64 / Mean I/σ(I) obs: 1.03 / % possible all: 73.2

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Processing

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

4gql


Resolution: 1.314→46.438 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.22 / Phase error: 20.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1913 3557 5 %Random
Rwork0.1526 ---
obs0.1545 71174 97.54 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.314→46.438 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 51 274 1567
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061455
X-RAY DIFFRACTIONf_angle_d1.0711990
X-RAY DIFFRACTIONf_dihedral_angle_d12.42526
X-RAY DIFFRACTIONf_chiral_restr0.071199
X-RAY DIFFRACTIONf_plane_restr0.005268
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3142-1.33220.4092930.37661706X-RAY DIFFRACTION62
1.3322-1.35120.33131280.33872423X-RAY DIFFRACTION87
1.3512-1.37140.31851360.29432611X-RAY DIFFRACTION94
1.3714-1.39280.2861460.29282754X-RAY DIFFRACTION99
1.3928-1.41570.29451460.25892715X-RAY DIFFRACTION99
1.4157-1.44010.23521480.23342783X-RAY DIFFRACTION99
1.4401-1.46630.24441460.21442803X-RAY DIFFRACTION100
1.4663-1.49450.24641410.20932737X-RAY DIFFRACTION100
1.4945-1.5250.25031430.19382785X-RAY DIFFRACTION100
1.525-1.55810.25541430.17892763X-RAY DIFFRACTION100
1.5581-1.59440.18061460.16422773X-RAY DIFFRACTION100
1.5944-1.63420.23041460.15282749X-RAY DIFFRACTION100
1.6342-1.67840.16661460.14992780X-RAY DIFFRACTION100
1.6784-1.72780.19661480.14992795X-RAY DIFFRACTION100
1.7278-1.78360.21171430.15312700X-RAY DIFFRACTION99
1.7836-1.84730.17891470.13482815X-RAY DIFFRACTION100
1.8473-1.92130.16351470.12612779X-RAY DIFFRACTION100
1.9213-2.00880.17361440.12052770X-RAY DIFFRACTION100
2.0088-2.11470.16431450.12352750X-RAY DIFFRACTION100
2.1147-2.24720.16411470.12522759X-RAY DIFFRACTION100
2.2472-2.42060.19351500.13632780X-RAY DIFFRACTION100
2.4206-2.66420.16361470.13882769X-RAY DIFFRACTION100
2.6642-3.04970.17941430.13872792X-RAY DIFFRACTION100
3.0497-3.8420.15691460.12732759X-RAY DIFFRACTION100
3.842-46.46670.1831420.14172767X-RAY DIFFRACTION99

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