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

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Basic information

Entry
Database: PDB / ID: 4gql
TitleCrystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470.1
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 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 / positive regulation of interferon-alpha production / collagen catabolic process / 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-[(S)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMINE / Chem-R47 / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.15 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 23, 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
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_alt_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_alt_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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _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)18,6857
Polymers17,6161
Non-polymers1,0696
Water5,459303
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.580, 63.390, 36.900
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-655-

HOH

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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-R47 / N-[(2S)-3-[(S)-(4-bromophenyl)(hydroxy)phosphoryl]-2-{[3-(3'-chlorobiphenyl-4-yl)-1,2-oxazol-5-yl]methyl}propanoyl]-L-alpha-glutamyl-L-alpha-glutamine / RXP470.1


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 818.004 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H35BrClN4O10P
References: N-[(2S)-3-[(S)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMINE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 303 / 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: 2.31 Å3/Da / Density % sol: 46.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Reservoir: 25% PEG 10000, 0.2M imidazole malate. Cryoprotectant: 27% PEG 8000, 15% MPEG 550, 10% glycerol, .01M hydroxamic acid, 90mM 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: ID23-1 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 23, 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: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.15→50 Å / Num. all: 58830 / Num. obs: 58014 / % possible obs: 98.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 13.934 Å2 / Rmerge(I) obs: 0.091 / Rsym value: 0.084 / Net I/σ(I): 15.78
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
1.15-1.226.731.32.31.2196.5
1.22-1.36.920.714.420.66199.9
1.3-1.416.980.387.40.351100
1.41-1.547.010.211.850.181100
1.54-1.727.040.11718.050.108199.9
1.72-1.996.980.07325.420.068199.9
1.99-2.446.760.05233.90.048199.8
2.44-3.446.760.03840.470.035199.1
3.44-505.770.03241.730.029182.4

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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: 3TSK

3tsk


Resolution: 1.15→32.599 Å / SU ML: 0.11 / Isotropic thermal model: Anisotropic / σ(F): 1.99 / Phase error: 15.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1545 2900 5 %
Rwork0.1333 --
obs0.1343 57994 98.69 %
all-58014 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.15→32.599 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1246 0 57 303 1606
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081517
X-RAY DIFFRACTIONf_angle_d1.52081
X-RAY DIFFRACTIONf_dihedral_angle_d15.377548
X-RAY DIFFRACTIONf_chiral_restr0.112200
X-RAY DIFFRACTIONf_plane_restr0.007275
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.15-1.16890.31861240.3122342X-RAY DIFFRACTION91
1.1689-1.1890.2321390.2522641X-RAY DIFFRACTION100
1.189-1.21070.23411370.22022613X-RAY DIFFRACTION100
1.2107-1.2340.25821380.21762638X-RAY DIFFRACTION100
1.234-1.25910.23751370.19462593X-RAY DIFFRACTION100
1.2591-1.28650.26521390.17612649X-RAY DIFFRACTION100
1.2865-1.31640.19111390.16422631X-RAY DIFFRACTION100
1.3164-1.34940.16241370.13862606X-RAY DIFFRACTION100
1.3494-1.38590.14091390.12612638X-RAY DIFFRACTION100
1.3859-1.42660.14951390.11822648X-RAY DIFFRACTION100
1.4266-1.47270.13071380.10812628X-RAY DIFFRACTION100
1.4727-1.52530.13381390.10652634X-RAY DIFFRACTION100
1.5253-1.58640.1261390.09822649X-RAY DIFFRACTION100
1.5864-1.65860.14161400.10162654X-RAY DIFFRACTION100
1.6586-1.7460.12491400.10612664X-RAY DIFFRACTION100
1.746-1.85540.12791390.10912636X-RAY DIFFRACTION100
1.8554-1.99860.12141410.11082670X-RAY DIFFRACTION100
1.9986-2.19970.12361410.11192695X-RAY DIFFRACTION100
2.1997-2.51790.13311420.11892684X-RAY DIFFRACTION100
2.5179-3.17190.14921440.12762732X-RAY DIFFRACTION99
3.1719-32.61250.17021290.15042449X-RAY DIFFRACTION85

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