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- PDB-5i2z: Crystal structure of the catalytic domain of MMP-12 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5i2z
TitleCrystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated triazole-linked carboxylate chelating water-soluble inhibitor (DC24).
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 / collagen catabolic process / extracellular matrix disassembly / positive regulation of interferon-alpha production / 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 / 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
S-1,2-PROPANEDIOL / Chem-V24 / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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 9, 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 1.3Feb 28, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_cell_line ..._entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _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

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)74,73032
Polymers70,4594
Non-polymers4,27228
Water8,701483
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6868
Polymers17,6151
Non-polymers1,0717
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6107
Polymers17,6151
Non-polymers9956
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6728
Polymers17,6151
Non-polymers1,0577
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,7649
Polymers17,6151
Non-polymers1,1498
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.990, 63.120, 78.750
Angle α, β, γ (deg.)90.00, 102.37, 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 / Fragment: UNP residues 106-263 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Details (production host): propagated in XL1-Blue / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: P39900, macrophage elastase

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Non-polymers , 7 types, 511 molecules

#2: Chemical
ChemComp-V24 / N-[([1,1'-biphenyl]-4-yl)sulfonyl]-N-({1-[3,4,6-tri-O-acetyl-2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl]-1H-1,2,3-triazol-4-yl}methyl)-D-valine


Mass: 743.781 Da / Num. of mol.: 4 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Formula: C34H41N5O12S / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Details (production host): propagated in XL1-Blue / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: macrophage elastase
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Formula: Ca
#5: Chemical ChemComp-PGO / S-1,2-PROPANEDIOL / Propanediol


Mass: 76.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 483 / 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: 2.8 Å3/Da / Density % sol: 56.02 % / Description: Thin plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein-ligand: hMMP12 F67D E219Q at 465 micro-M, 20 milli-M acetohydroxamic acid in 0.020M Tris-HCl, 3 milli-M CaCl2, 0.2M NaCl, pH 7.5, 0.2 milli-M inhibitor (DC24) 10% DMSO Precipitant: ...Details: Protein-ligand: hMMP12 F67D E219Q at 465 micro-M, 20 milli-M acetohydroxamic acid in 0.020M Tris-HCl, 3 milli-M CaCl2, 0.2M NaCl, pH 7.5, 0.2 milli-M inhibitor (DC24) 10% DMSO Precipitant: 35% PEG4K, 0.2M imidazole piperidine, 15% dioxane, pH 8.5. Cryoprotectant: 40% cryomix: (25 % diethylene glycol + 12.5 % glycerol + 25 % 1,2-propanediol + 12.5 % 1,4-dioxane) 25% PEG 6K, 100mM TRIS HCl, pH 8.0
PH range: 8.0-8.5 / 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: 2.29→48.79 Å / Num. obs: 27728 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 4.6 % / Biso Wilson estimate: 28.71 Å2 / Rmerge(I) obs: 0.183 / Rsym value: 0.162 / Net I/σ(I): 6.53
Reflection shellResolution: 2.29→2.35 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.539 / Mean I/σ(I) obs: 2.96 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IOL

5iol


Resolution: 2.3→44.41 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 30.09
RfactorNum. reflection% reflection
Rfree0.263 1367 5 %
Rwork0.214 --
obs0.217 27354 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.3→44.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4929 0 246 483 5658
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.015372
X-RAY DIFFRACTIONf_angle_d1.4227306
X-RAY DIFFRACTIONf_dihedral_angle_d18.4411877
X-RAY DIFFRACTIONf_chiral_restr0.062751
X-RAY DIFFRACTIONf_plane_restr0.007951
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2998-2.3820.32231360.21872585X-RAY DIFFRACTION100
2.382-2.47730.28221340.21122560X-RAY DIFFRACTION100
2.4773-2.59010.26551360.20592593X-RAY DIFFRACTION100
2.5901-2.72660.27141380.21442625X-RAY DIFFRACTION100
2.7266-2.89740.28071360.21842570X-RAY DIFFRACTION100
2.8974-3.12110.30211360.2182580X-RAY DIFFRACTION100
3.1211-3.43510.27851370.20122600X-RAY DIFFRACTION100
3.4351-3.93190.23291360.19182617X-RAY DIFFRACTION99
3.9319-4.95270.21311370.19262604X-RAY DIFFRACTION99
4.9527-44.42160.2791410.26942653X-RAY DIFFRACTION99

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