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- PDB-5i3m: Crystal structure of the catalytic domain of MMP-12 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5i3m
TitleCrystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated thiourea-linked carboxylate zinc-chelator water-soluble inhibitor (DC31).
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / Inhibitor / complex / glycoconjugate / metalloprotease
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 / 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-67F / 1,4-DIETHYLENE DIOXIDE / S-1,2-PROPANEDIOL / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsStura, E.A. / Rosalia, L. / Cuffaro, D. / Tepshi, L. / Ciccone, L. / Rossello, A.
CitationJournal: Chemmedchem / Year: 2016
Title: Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.
Authors: Nuti, E. / Cuffaro, D. / D'Andrea, F. / Rosalia, L. / Tepshi, L. / Fabbi, M. / Carbotti, G. / Ferrini, S. / Santamaria, S. / Camodeca, C. / Ciccone, L. / Orlandini, E. / Nencetti, S. / ...Authors: Nuti, E. / Cuffaro, D. / D'Andrea, F. / Rosalia, L. / Tepshi, L. / Fabbi, M. / Carbotti, G. / Ferrini, S. / Santamaria, S. / Camodeca, C. / Ciccone, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Dive, V. / Rossello, A.
History
DepositionFeb 10, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2016Group: Database references
Revision 1.2Aug 17, 2016Group: Database references
Revision 1.3Jan 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.ptnr1_auth_asym_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_asym_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
B: Macrophage metalloelastase
C: Macrophage metalloelastase
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,65336
Polymers70,4594
Non-polymers4,19432
Water7,746430
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6599
Polymers17,6151
Non-polymers1,0448
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,75710
Polymers17,6151
Non-polymers1,1429
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6559
Polymers17,6151
Non-polymers1,0408
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5838
Polymers17,6151
Non-polymers9687
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.720, 63.140, 78.920
Angle α, β, γ (deg.)90.00, 103.09, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 17614.684 Da / Num. of mol.: 4 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Details: macrophage elastase / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli (E. coli) / References: UniProt: P39900, macrophage elastase

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Non-polymers , 8 types, 462 molecules

#2: Chemical
ChemComp-67F / (2S)-2-{[2-({[(2R,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]carbamothioyl}amino)ethyl](biphenyl-4-ylsulfonyl)amino}-3-methylbutanoic acid (non-preferred name)


Mass: 638.753 Da / Num. of mol.: 4 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Formula: C28H38N4O9S2 / Details: macrophage elastase / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Production host: Escherichia coli (E. coli) / References: macrophage elastase
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PGO / S-1,2-PROPANEDIOL


Mass: 76.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2
#7: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H8O2
#8: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 430 / 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: 2.19 Å3/Da / Density % sol: 43.96 % / Description: thin flat plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein-ligand: hMMP12 F67D E219Q 465 micro-M, 0.02M acetohydroxamic acid 0.5 milli-M inhibitor (DC31) 10% DMSO. Precipitant: 32.4% PEG 4K, 8% dioxane, 0.2M imidazole piperidine, pH 8.5. ...Details: Protein-ligand: hMMP12 F67D E219Q 465 micro-M, 0.02M acetohydroxamic acid 0.5 milli-M inhibitor (DC31) 10% DMSO. Precipitant: 32.4% PEG 4K, 8% dioxane, 0.2M imidazole piperidine, pH 8.5. Cryoprotectant: 40% cryomix:(12.5 % diethylene glycol + 12.5 % glycerol + 12.5 % 1,2-propanediol + 25 % DMSO + 25 % 1,4-dioxane) 12% PEG 4K, 10% Dioxane, 0.1 M imidazole piperidine pH 8.5.
PH range: 8.5 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryonozzle
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 8, 2015 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.17→48.79 Å / Num. obs: 32560 / % possible obs: 99.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.34 % / Biso Wilson estimate: 33.956 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.1 / Rsym value: 0.096 / Net I/av σ(I): 12.748 / Net I/σ(I): 9.44
Reflection shellResolution: 2.17→2.23 Å / Redundancy: 3.73 % / Rmerge(I) obs: 0.523 / Mean I/σ(I) obs: 3.06 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PHENIXrefinement
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I2Z

5i2z


Resolution: 2.17→48.79 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.929 / SU B: 7.178 / SU ML: 0.181 / Cross valid method: THROUGHOUT / ESU R: 0.38 / ESU R Free: 0.24 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25324 1617 5 %RANDOM
Rwork0.20615 ---
obs0.2085 30719 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 36.572 Å2
Baniso -1Baniso -2Baniso -3
1--1.53 Å20 Å20.98 Å2
2---3.8 Å2-0 Å2
3---4.4 Å2
Refinement stepCycle: 1 / Resolution: 2.17→48.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4936 0 60 430 5426
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0195350
X-RAY DIFFRACTIONr_bond_other_d0.0060.024855
X-RAY DIFFRACTIONr_angle_refined_deg1.9041.9547259
X-RAY DIFFRACTIONr_angle_other_deg1.054311126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9075634
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.21623.071254
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.39815767
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8181530
X-RAY DIFFRACTIONr_chiral_restr0.1160.2753
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.026136
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021402
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9393.2772533
X-RAY DIFFRACTIONr_mcbond_other2.9383.2762532
X-RAY DIFFRACTIONr_mcangle_it4.2284.8963168
X-RAY DIFFRACTIONr_mcangle_other4.2294.8973169
X-RAY DIFFRACTIONr_scbond_it3.683.9592817
X-RAY DIFFRACTIONr_scbond_other3.6793.9592818
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.6525.7794092
X-RAY DIFFRACTIONr_long_range_B_refined8.18328.8046569
X-RAY DIFFRACTIONr_long_range_B_other8.02328.5896430
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.17→2.226 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 118 -
Rwork0.284 2245 -
obs--99.04 %

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