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- PDB-2hu6: Crystal structure of human MMP-12 in complex with acetohydroxamic... -

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Basic information

Entry
Database: PDB / ID: 2hu6
TitleCrystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / MMP-12 / matrix metalloproteinase / macrophage metalloelastase / inhibitor / hydroxamic acid / drug design
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 / 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-37A / ACETOHYDROXAMIC ACID / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.32 Å
AuthorsMannino, C. / Nievo, M. / Machetti, F. / Papakyriakou, A. / Calderone, V. / Fragai, M. / Guarna, A.
Citation
Journal: Bioorg.Med.Chem. / Year: 2006
Title: Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.
Authors: Mannino, C. / Nievo, M. / Machetti, F. / Papakyriakou, A. / Calderone, V. / Fragai, M. / Guarna, A.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2005
Title: Conformational variability of matrix metalloproteinases: beyond a single 3D structure.
Authors: Bertini, I. / Calderone, V. / Cosenza, M. / Fragai, M. / Lee, Y.-M. / Luchinat, C. / Mangani, S. / Turano, P.
History
DepositionJul 26, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 19, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Jan 24, 2018Group: Database references / Category: citation_author / Item: _citation_author.name
Revision 1.5Oct 20, 2021Group: Data collection / Database references / Derived calculations
Category: database_2 / diffrn_source ...database_2 / diffrn_source / 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 / _diffrn_source.pdbx_synchrotron_site / _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_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3258
Polymers17,6161
Non-polymers7107
Water4,612256
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.250, 60.179, 53.974
Angle α, β, γ (deg.)90.00, 114.59, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-480-

HOH

21A-483-

HOH

31A-500-

HOH

41A-543-

HOH

51A-617-

HOH

DetailsThe protein is monomeric in vivo and there is one molecule in the asymmetric unit.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Macrophage metalloelastase / HME / Matrix metalloproteinase-12 / MMP-12 / Macrophage elastase / ME


Mass: 17615.670 Da / Num. of mol.: 1 / Fragment: Catalytic Domain (residues 106-263) / Mutation: F171D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Plasmid: pET21 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P39900, macrophage elastase

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Non-polymers , 5 types, 263 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-37A / (1S,5S,7R)-N~7~-(BIPHENYL-4-YLMETHYL)-N~3~-HYDROXY-6,8-DIOXA-3-AZABICYCLO[3.2.1]OCTANE-3,7-DICARBOXAMIDE / (1S,5S,7R)-3-AZA-6,8-DIOXA-BICYCLO[3.2.1]OCTANE-3,7-DICARBOXYLIC ACID 7-[(BIPHENYL-4-YLMETHYL)-AMIDE]-3-HYDROXYAMIDE


Mass: 383.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N3O5
#5: Chemical ChemComp-HAE / ACETOHYDROXAMIC ACID


Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2 / Comment: inhibitor, medication*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 2.15 Å3/Da / Density % sol: 42.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1 M Tris-HCl, 30% PEG 6000, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: BW7A / Wavelength: 0.9392 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 26, 2005
Details: Fixed exit double crystal Si [111], horizontally focusing
RadiationMonochromator: Fixed exit double crystal Si [111], horizontally focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9392 Å / Relative weight: 1
ReflectionResolution: 1.32→49.08 Å / Num. all: 34648 / Num. obs: 34648 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Biso Wilson estimate: 10.41 Å2 / Rmerge(I) obs: 0.053 / Rsym value: 0.053 / Net I/σ(I): 8.6
Reflection shellResolution: 1.32→1.39 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.282 / Mean I/σ(I) obs: 2.1 / Num. unique all: 4823 / Rsym value: 0.282 / % possible all: 95.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MAR345345DTBdata collection
MOSFLMdata reduction
CCP4(SCALA)data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1Y93

1y93


Resolution: 1.32→25.68 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 1.57 / SU ML: 0.03 / Isotropic thermal model: Anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.064 / ESU R Free: 0.055 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18176 3144 9.1 %RANDOM
Rwork0.16062 ---
all0.16256 31503 --
obs0.16256 31503 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 13.577 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20 Å2-0.33 Å2
2---0.11 Å20 Å2
3----0.44 Å2
Refine analyzeLuzzati sigma a obs: 0.03 Å
Refinement stepCycle: LAST / Resolution: 1.32→25.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1238 0 38 256 1532
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0211310
X-RAY DIFFRACTIONr_angle_refined_deg1.11.9431777
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.725157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.44923.17563
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.3315188
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.79157
X-RAY DIFFRACTIONr_chiral_restr0.0770.2181
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021042
X-RAY DIFFRACTIONr_nbd_refined0.1830.2669
X-RAY DIFFRACTIONr_nbtor_refined0.3080.2923
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1150.2150
X-RAY DIFFRACTIONr_metal_ion_refined0.0740.218
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.268
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1210.237
X-RAY DIFFRACTIONr_mcbond_it0.761.5796
X-RAY DIFFRACTIONr_mcangle_it1.11521242
X-RAY DIFFRACTIONr_scbond_it1.8373588
X-RAY DIFFRACTIONr_scangle_it2.3484.5535
X-RAY DIFFRACTIONr_rigid_bond_restr1.75131384
X-RAY DIFFRACTIONr_sphericity_free2.6143262
X-RAY DIFFRACTIONr_sphericity_bonded1.8631271
LS refinement shellResolution: 1.32→1.354 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.285 220 -
Rwork0.229 2119 -
obs--100 %

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