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- PDB-4gr0: Crystal structure of the catalytic domain of Human MMP12 in compl... -

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Basic information

Entry
Database: PDB / ID: 4gr0
TitleCrystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470B
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-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALANYL-L-ALANINAMIDE / Chem-R4B / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.497 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)18,5697
Polymers17,6161
Non-polymers9536
Water3,477193
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.770, 62.760, 37.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Macrophage metalloelastase / MME / Macrophage elastase / ME / 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: HME, MMP12 / Plasmid: PET24A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / 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-R4B / N-[(2S)-3-[(R)-(4-bromophenyl)(hydroxy)phosphoryl]-2-{[3-(3'-chlorobiphenyl-4-yl)-1,2-oxazol-5-yl]methyl}propanoyl]-L-a lanyl-L-alaninamide / RXP470B


Type: peptide-like, Peptide-like / Class: Enzyme inhibitor / Mass: 701.932 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H31BrClN4O6P
References: N-[(2S)-3-[(R)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALANYL-L-ALANINAMIDE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 2.35 Å3/Da / Density % sol: 47.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein complex: hMMP12 F171D 855 microM, inhibitor 0.788 milliM. Reservoir: 35% PEG 4,000 0.2M imidazole malate pH 8.5. Drops: 1 microL protein complex + 1 microL reservoir. Cryoprotectant: ...Details: Protein complex: hMMP12 F171D 855 microM, inhibitor 0.788 milliM. Reservoir: 35% PEG 4,000 0.2M imidazole malate pH 8.5. Drops: 1 microL protein complex + 1 microL reservoir. Cryoprotectant: 40% MPEG 5K, 10% 1,2-propanediol, (10% (Na acetate, ADA, Bicine) 90% at pH 4/ 10% at pH 9.0). Flash freezing in Liquid N2, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.9334 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Apr 24, 2010 / Details: mirrors
RadiationMonochromator: Diamond (111), Ge(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9334 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. all: 27502 / Num. obs: 26347 / % possible obs: 95.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.51 % / Biso Wilson estimate: 20.815 Å2 / Rmerge(I) obs: 0.111 / Rsym value: 0.0976 / Net I/σ(I): 9.33
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.5-1.592.881.041.1943880.84977.7
1.59-1.73.580.7472.0940860.63698.2
1.7-1.833.660.4993.2338540.42799.3
1.83-2.013.660.26635480.22399.2
2.01-2.243.640.14910.0932320.12899.5
2.24-2.593.630.10113.5928560.08699.6
2.59-3.173.610.06319.6824730.05399.6
3.17-4.473.520.04229.1719210.03699.7
4.47-503.250.0431.5911440.03398.8

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Processing

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

4gql


Resolution: 1.497→32.406 Å / SU ML: 0.17 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 1.99 / σ(I): -3 / Phase error: 23.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2178 1317 5 %RANDOM
Rwork0.1864 ---
obs0.188 26336 95.79 %-
all-26347 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 11.4 Å2
Refinement stepCycle: LAST / Resolution: 1.497→32.406 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1246 0 49 193 1488
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061394
X-RAY DIFFRACTIONf_angle_d1.1071905
X-RAY DIFFRACTIONf_dihedral_angle_d15.251487
X-RAY DIFFRACTIONf_chiral_restr0.077191
X-RAY DIFFRACTIONf_plane_restr0.006253
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.497-1.55690.39711100.31882095209573
1.5569-1.62770.32821390.28082648264893
1.6277-1.71360.28471490.24812830283099
1.7136-1.82090.2631490.21822825282599
1.8209-1.96150.20931510.19272860286099
1.9615-2.15880.20841510.16828772877100
2.1588-2.47110.20821520.172328962896100
2.4711-3.1130.19771540.168429152915100
3.113-32.41310.1771620.156630733073100

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