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- PDB-5cxa: Crystal structure of the catalytic domain of Human MMP12 in compl... -

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Basic information

Entry
Database: PDB / ID: 5cxa
TitleCrystal structure of the catalytic domain of Human MMP12 in complex with a carboxylate inhibitor related to RXP470
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / metzincin / RXP470 / carboxylate based inhibitor / carboxylate peptidic inhibitor
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 / cellular response to virus / metalloendopeptidase activity / 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-55L / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 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
DepositionJul 28, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 10, 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 / 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)18,4527
Polymers17,5581
Non-polymers8946
Water5,134285
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-23 kcal/mol
Surface area8090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.230, 63.700, 36.620
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-431-

HOH

21A-479-

HOH

31A-681-

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 K241A mutant for calorimetric studies / 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-55L / (R)-4-(((S)-1-(((S)-1-amino-4-carboxy-1-oxobutan-2-yl)amino)-4-carboxy-1-oxobutan-2-yl)amino)-3-((3-(3'-chloro-[1,1'-biphenyl]-4-yl)isoxazol-5-yl)methyl)-4-oxobutanoate / MME / Macrophage elastase / hME / Matrix metalloproteinase-12 / MMP-12


Mass: 643.041 Da / Num. of mol.: 1 / Fragment: UNP residues 107-263 / Mutation: F171D, K241A
Source method: isolated from a genetically manipulated source
Formula: C30H31ClN4O10 / Details: MMP12 F171D K241A mutant for calorimetric studies / Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Plasmid: PET24A / Production host: Escherichia coli BL21(DE3) (bacteria) / References: macrophage elastase
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 285 / 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: 2.29 Å3/Da / Density % sol: 46.18 % / Description: prismatic
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 10
Details: Protein: hMMP12 F171D K241A at 608 micro-M + 10 milli-M AHA + 0.552 milli-M inhibitor. precipitant: 26% PEG4000, 3% dioxane, 0.114 M TRIS pH 10. cryoprotectant: 10 % diethylene glycol + 5 % ...Details: Protein: hMMP12 F171D K241A at 608 micro-M + 10 milli-M AHA + 0.552 milli-M inhibitor. precipitant: 26% PEG4000, 3% dioxane, 0.114 M TRIS pH 10. cryoprotectant: 10 % diethylene glycol + 5 % glycerol + 10 % 2,3-butanediol + 5 % 1,4-dioxane, 25% PEG 6K, 0.1 M TRIS-HCl, pH 8.0
PH range: 8-10 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 stream
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8729 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 7, 2014 / Details: bent cylindrical mirror
RadiationMonochromator: horizontally diffracting Si (111) monochromator and Pt coated mirrors in Kirkpatrick-Baez geometry for focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8729 Å / Relative weight: 1
ReflectionResolution: 1.3→46.88 Å / Num. all: 40627 / Num. obs: 40584 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 9.05 % / Rmerge(I) obs: 0.165 / Rsym value: 0.155 / Net I/σ(I): 9.23
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 8.67 % / Rmerge(I) obs: 1.39 / Mean I/σ(I) obs: 1.24 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
Cootmodel building
XDSdata reduction
MxCuBEdata collection
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQL

4gql


Resolution: 1.3→36.62 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 17.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.181 2030 5 %RANDOM
Rwork0.1403 ---
obs0.1423 40581 99.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.3→36.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 50 285 1577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051436
X-RAY DIFFRACTIONf_angle_d0.8481958
X-RAY DIFFRACTIONf_dihedral_angle_d26.262507
X-RAY DIFFRACTIONf_chiral_restr0.076191
X-RAY DIFFRACTIONf_plane_restr0.005262
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3001-1.33260.31591410.26372662X-RAY DIFFRACTION98
1.3326-1.36860.30151430.24042724X-RAY DIFFRACTION100
1.3686-1.40890.27741430.21522721X-RAY DIFFRACTION100
1.4089-1.45440.22641420.18732704X-RAY DIFFRACTION100
1.4544-1.50640.21751450.17442744X-RAY DIFFRACTION100
1.5064-1.56670.21641430.15592715X-RAY DIFFRACTION100
1.5667-1.6380.1961430.14332724X-RAY DIFFRACTION100
1.638-1.72430.18241440.12912733X-RAY DIFFRACTION100
1.7243-1.83240.17461460.12542771X-RAY DIFFRACTION100
1.8324-1.97380.17221430.1192729X-RAY DIFFRACTION100
1.9738-2.17240.15691470.1182775X-RAY DIFFRACTION100
2.1724-2.48670.19191460.12512781X-RAY DIFFRACTION100
2.4867-3.13280.16421480.13372818X-RAY DIFFRACTION100
3.1328-36.63450.14741560.12882950X-RAY DIFFRACTION100

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