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- PDB-3ts4: Human MMP12 in complex with L-glutamate motif inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ts4
TitleHuman MMP12 in complex with L-glutamate motif inhibitor
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / pseudo dipeptides / potent inhibitors / metzincin / Zinc protease / HYDROLASE-HYDROLASE INHIBITOR complex
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
N-{3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMYL-AMIDE / Chem-EEG / IMIDAZOLE / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.587 Å
AuthorsStura, E.A. / Dive, V. / Devel, L. / Czarny, B. / Beau, F. / Vera, L.
CitationJournal: J.Biol.Chem. / Year: 2012
Title: Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.
Authors: Devel, L. / Beau, F. / Amoura, M. / Vera, L. / Cassar-Lajeunesse, E. / Garcia, S. / Czarny, B. / Stura, E.A. / Dive, V.
History
DepositionSep 12, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 17, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Sep 13, 2023Group: 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 / struct_ref_seq_dif / struct_site
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_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

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5949
Polymers17,6161
Non-polymers9788
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.090, 63.650, 37.370
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: 17615.670 Da / Num. of mol.: 1 / Fragment: catalitic subunit (UNP RESIDUES 106-263) / Mutation: F171D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HME, MMP12 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P39900, macrophage elastase

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Non-polymers , 6 types, 221 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-EEG / N-{3-[4-(4-phenylthiophen-2-yl)phenyl]propanoyl}-L-alpha-glutamyl-L-alpha-glutamyl-amide


Type: Peptide-like / Class: Inhibitor / Mass: 565.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31N3O7S
References: N-{3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMYL-AMIDE
#5: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.37 Å3/Da / Density % sol: 48.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: MMP12 AT 0.4 mM co-crystallization, with 100mM AHA and non-chelating inhibitor EEG at 1.1 mM with reservoir: 27% PEG 10K, 0.1M glycine. AHA removed during cryo-soak for 5 min in 30% MPEG2K, ...Details: MMP12 AT 0.4 mM co-crystallization, with 100mM AHA and non-chelating inhibitor EEG at 1.1 mM with reservoir: 27% PEG 10K, 0.1M glycine. AHA removed during cryo-soak for 5 min in 30% MPEG2K, 10% ethylene glycol, 200 mM imidazole malate, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9919 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 20, 2009 / 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: 0.9919 Å / Relative weight: 1
ReflectionResolution: 1.59→33 Å / Num. all: 23301 / Num. obs: 23208 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.67 % / Biso Wilson estimate: 25.7 Å2 / Rmerge(I) obs: 0.099 / Rsym value: 0.081 / Net I/σ(I): 16.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.59-1.687.580.6322.8936870.80598.8
4.72-336.860.01940.169930.04194.7
3.35-4.727.310.0240.1616510.04599.8
2.74-3.357.520.0332.3420710.058100
2.38-2.747.750.04824.4124350.078100
2.13-2.387.790.06818.6827400.108100
1.94-2.137.860.10213.429970.156100
1.8-1.947.840.2038.1332460.27100
1.68-1.87.780.3664.8734890.48299.9

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Processing

Software
NameVersionClassification
DNAdata collection
MOLREPphasing
PHENIX(phenix.refine)refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LIK

3lik


Resolution: 1.587→32.976 Å / SU ML: 0.39 / Isotropic thermal model: anisotropic (TLS) / Cross valid method: THROUGHOUT / σ(F): 2.01 / Phase error: 19.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.203 1160 5 %RANDOM
Rwork0.1784 ---
obs0.1797 23181 99.51 %-
all-23295 --
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 53.451 Å2 / ksol: 0.333 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.3654 Å2-0 Å2-0 Å2
2---0.1928 Å20 Å2
3----0.1726 Å2
Refinement stepCycle: LAST / Resolution: 1.587→32.976 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1246 0 56 213 1515
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0161398
X-RAY DIFFRACTIONf_angle_d1.6121899
X-RAY DIFFRACTIONf_dihedral_angle_d18.681482
X-RAY DIFFRACTIONf_chiral_restr0.095188
X-RAY DIFFRACTIONf_plane_restr0.005253
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5871-1.65940.29661400.27622654X-RAY DIFFRACTION98
1.6594-1.74680.25711440.22712730X-RAY DIFFRACTION100
1.7468-1.85630.2061430.19842736X-RAY DIFFRACTION100
1.8563-1.99960.18571430.17762724X-RAY DIFFRACTION100
1.9996-2.20080.2141460.1772755X-RAY DIFFRACTION100
2.2008-2.51910.21041440.18132742X-RAY DIFFRACTION100
2.5191-3.17340.22221480.17572806X-RAY DIFFRACTION100
3.1734-32.98280.17391520.1592874X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 7.2644 Å / Origin y: 15.892 Å / Origin z: 3.0981 Å
111213212223313233
T0.0757 Å20.0174 Å20.0131 Å2-0.0471 Å20.0461 Å2--0.0157 Å2
L6.4628 °20.174 °20.6073 °2-1.5624 °20.004 °2--1.1953 °2
S-0.0246 Å °-0.3765 Å °-0.3007 Å °0.077 Å °0.0391 Å °0.0268 Å °0.0388 Å °-0.0831 Å °-0.0129 Å °
Refinement TLS groupSelection details: all

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