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- PDB-4gr8: Crystal structure of the catalytic domain of Human MMP12 in compl... -

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Basic information

Entry
Database: PDB / ID: 4gr8
TitleCrystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470C
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / potent selective phosphinic inhibitor / METZINCIN / Zinc protease / HYDROLASE-HYDROLASE INHIBITOR complex
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
N-{(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-[(3-PHENYL-1,2-OXAZOL-5-YL)METHYL]PROPANOYL}-L-ALANYL-L-ALANINAMIDE / IMIDAZOLE / Chem-R4C / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.299 Å
AuthorsStura, E.A. / Vera, L. / Beau, F. / Devel, L. / Cassar-Lajeunesse, E. / Dive, V.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
Authors: Czarny, B. / Stura, E.A. / Devel, L. / Vera, L. / Cassar-Lajeunesse, E. / Beau, F. / Calderone, V. / Fragai, M. / Luchinat, C. / Dive, V.
History
DepositionAug 24, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2013Provider: repository / Type: Initial release
Revision 1.1May 22, 2013Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)17,7428
Polymers16,8311
Non-polymers9127
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.830, 61.470, 33.460
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 16830.721 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 111-262) / Mutation: F171D
Source method: isolated from a genetically manipulated source
Details: N-TERMINAL MISSING RESIDUES (106-110) ARE DUE TO SELF-PROTEOLYSIS. C-terminal glycine 263 has also been proteolyzed.
Source: (gene. exp.) Homo sapiens (human) / Gene: HME, MMP12 / Plasmid: PET24A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P39900, macrophage elastase

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Non-polymers , 5 types, 204 molecules

#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-R4C / N-{(2S)-3-[(R)-(4-bromophenyl)(hydroxy)phosphoryl]-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoyl}-L-alanyl-L-alaninamid e / RXP470C


Type: peptide-like, Peptide-like / Class: Enzyme inhibitor / Mass: 591.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28BrN4O6P
References: N-{(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-[(3-PHENYL-1,2-OXAZOL-5-YL)METHYL]PROPANOYL}-L-ALANYL-L-ALANINAMIDE
#5: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#6: 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: 2.07 Å3/Da / Density % sol: 40.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: protein: hMMP12 F171D 848 microM. reservoir: 24% PEG 10000, 0.2 M imidazole malate pH 8.5. CRYOPROTECTANT: 27% PEG 8000, 15% monomethyl-PEG 550, 10% glycerol, 0.09 M Tris-HCl, pH 8.0, VAPOR ...Details: protein: hMMP12 F171D 848 microM. reservoir: 24% PEG 10000, 0.2 M imidazole malate pH 8.5. CRYOPROTECTANT: 27% PEG 8000, 15% monomethyl-PEG 550, 10% glycerol, 0.09 M Tris-HCl, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 24, 2010 / Details: mirrors
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.3→50 Å / Num. all: 35305 / Num. obs: 35086 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -4 / Redundancy: 7.56 % / Biso Wilson estimate: 17.669 Å2 / Rmerge(I) obs: 0.098 / Rsym value: 0.091 / Net I/σ(I): 12.84
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.3-1.387.160.862.4756020.79897.7
1.38-1.477.780.573.952970.54199.9
1.47-1.597.80.3785.9449510.353100
1.59-1.747.840.2528.6945450.236100
1.74-1.957.750.15513.8541580.14499.9
1.95-2.257.590.09721.2836650.0999.8
2.25-2.757.380.07526.3531370.0799.9
2.75-3.887.110.05332.424890.04999.9
3.88-506.960.04335.314610.0494.9

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Processing

Software
NameVersionClassification
CBASSdata collection
MOLREPphasing
PHENIX(phenix.refine: 1.8_1069)refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQL

4gql


Resolution: 1.299→30.008 Å / SU ML: 0.09 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 1.99 / σ(I): -3 / Phase error: 19.25 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2027 1753 5 %RANDOM
Rwork0.1767 ---
obs0.178 35069 99.37 %-
all-35086 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.299→30.008 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1191 0 47 197 1435
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061338
X-RAY DIFFRACTIONf_angle_d1.1541824
X-RAY DIFFRACTIONf_dihedral_angle_d16.521463
X-RAY DIFFRACTIONf_chiral_restr0.077185
X-RAY DIFFRACTIONf_plane_restr0.006244
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.2988-1.33390.2791250.26612411241196
1.3339-1.37320.26611340.235325462546100
1.3732-1.41750.23981330.219425262526100
1.4175-1.46810.23951340.20825402540100
1.4681-1.52690.24211350.205725532553100
1.5269-1.59640.20341340.18525562556100
1.5964-1.68060.20671350.177825542554100
1.6806-1.78590.1831340.179425472547100
1.7859-1.92370.19991350.165825692569100
1.9237-2.11730.1971370.16525982598100
2.1173-2.42350.19131360.169725932593100
2.4235-3.05290.20911390.17226352635100
3.0529-30.01560.17891420.15772688268897

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