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- PDB-5i43: Crystal structure of the catalytic domain of MMP-12 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5i43
TitleCrystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated triazole-linked carboxylate chelator water-soluble inhibitor (DC32).
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 / 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
Chem-67M / S-1,2-PROPANEDIOL / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 11, 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 24, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name ..._entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain / _entity_src_gen.pdbx_host_org_variant
Revision 1.4Jan 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

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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)76,71159
Polymers70,4594
Non-polymers6,25255
Water10,719595
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A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,28817
Polymers17,6151
Non-polymers1,67416
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,13214
Polymers17,6151
Non-polymers1,51713
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,17414
Polymers17,6151
Non-polymers1,56013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,11614
Polymers17,6151
Non-polymers1,50113
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.030, 63.660, 79.030
Angle α, β, γ (deg.)90.00, 103.03, 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: Fragment: catalitic subunit (UNP RESIDUES 106-263) / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: P39900, macrophage elastase

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Non-polymers , 7 types, 650 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-67M / (2R)-2-[({1-[3-({(2R,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)propyl]-1H-1,2,3-triazol-4-yl}methyl)(biphenyl-4-ylsulfonyl)amino]-3-methylbutanoic acid (non-preferred name)


Mass: 801.860 Da / Num. of mol.: 4 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Formula: C37H47N5O13S / Details: Fragment: catalitic subunit (UNP RESIDUES 106-263) / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: macrophage elastase
#5: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 23 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 76.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 595 / 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: 2.2 Å3/Da / Density % sol: 44.2 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein-ligand: hMMP12 F171D E219Q 465 micro-M in 0.020 M Tris-HCl, 3 milli-M CaCl2, 0.2 M NaCl, 0.02 M acetohydroxamic acid, 10% DMSO, pH 7.5, 0.5 milli-M inhibitor (DC31). Precipitant: 40% ...Details: Protein-ligand: hMMP12 F171D E219Q 465 micro-M in 0.020 M Tris-HCl, 3 milli-M CaCl2, 0.2 M NaCl, 0.02 M acetohydroxamic acid, 10% DMSO, pH 7.5, 0.5 milli-M inhibitor (DC31). Precipitant: 40% PEG4K, 9% dioxane, 0.18 M imidazole piperidine, pH 8.5. Cryoprotectant: 40% cryomix SM2:(12.5 % ethylene glycol + 12.5 % glycerol + 12.5 % 1,2-propanediol + 25 % DMSO + 37.5 % 1,4-dioxane), 22.5% MPEG 4K, 5% dioxane, 100 mM 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
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.95→44.56 Å / Num. obs: 45366 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.97 % / Biso Wilson estimate: 26.387 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.172 / Rsym value: 0.167 / Net I/av σ(I): 12.744 / Net I/σ(I): 7.24
Reflection shellResolution: 1.95→2 Å / Redundancy: 3.96 % / Rmerge(I) obs: 0.716 / Mean I/σ(I) obs: 2.02 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I3M

5i3m


Resolution: 1.95→44.56 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.938 / SU B: 4.535 / SU ML: 0.127 / Cross valid method: THROUGHOUT / ESU R: 0.224 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23323 2264 5 %RANDOM
Rwork0.20039 ---
obs0.20205 43013 99.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.062 Å2
Baniso -1Baniso -2Baniso -3
1--1.32 Å2-0 Å20.39 Å2
2---1.68 Å2-0 Å2
3---2.55 Å2
Refinement stepCycle: LAST / Resolution: 1.95→44.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5124 0 206 595 5925
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0195526
X-RAY DIFFRACTIONr_bond_other_d0.0040.025060
X-RAY DIFFRACTIONr_angle_refined_deg1.9891.9727456
X-RAY DIFFRACTIONr_angle_other_deg1.073311579
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0855644
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.10123.113257
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.6115775
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3641530
X-RAY DIFFRACTIONr_chiral_restr0.1190.2761
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.026259
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021401
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_it2.3672.2122567
X-RAY DIFFRACTIONr_mcbond_other2.3642.2112566
X-RAY DIFFRACTIONr_mcangle_it3.4493.2963214
X-RAY DIFFRACTIONr_mcangle_other3.453.2973215
X-RAY DIFFRACTIONr_scbond_it3.6042.9062959
X-RAY DIFFRACTIONr_scbond_other3.6032.9062959
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.5154.1534243
X-RAY DIFFRACTIONr_long_range_B_refined8.39920.6186787
X-RAY DIFFRACTIONr_long_range_B_other8.17720.1136583
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 166 -
Rwork0.32 3157 -
obs--99.76 %

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