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- PDB-3n2u: Crystal structure of the catalytic domain of human MMP12 complexe... -

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Basic information

Entry
Database: PDB / ID: 3n2u
TitleCrystal structure of the catalytic domain of human MMP12 complexed with the inhibitor N-hydroxy-2-(4-methoxy-N(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)phenylsulfonamido)acetamide
ComponentsMacrophage metalloelastase
KeywordsHydrolase/Hydrolase inhibitor / MATRIX METALLOPROTEINASE / MMP12 / ELASTASE / COMPLEX (ELASTASE-INHIBITOR) / METALLO ELASTASE / EXTRACELLULAR MATRIX / GLYCOPROTEIN / HYDROLASE / METAL-INDING / METALLOPROTEASE / PROTEASE / SECRETED / ZYMOGEN / 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 / 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-D3X / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsCalderone, V.
Citation
Journal: Eur.J.Med.Chem. / Year: 2010
Title: Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs).
Authors: Attolino, E. / Calderone, V. / Dragoni, E. / Fragai, M. / Richichi, B. / Luchinat, C. / Nativi, C.
#1: Journal: J.Am.Chem.Soc. / Year: 2007
Title: Exploring the subtleties of drug-receptor interactions: the case of matrix metalloproteinases.
Authors: Bertini, I. / Calderone, V. / Fragai, M. / Giachetti, A. / Loconte, M. / Luchinat, C. / Maletta, M. / Nativi, C. / Yeo, K.J.
History
DepositionMay 19, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 6, 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_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_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
A: N-hydroxy-2-{[(4-methoxyphenyl)sulfonyl](2-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}ethyl)amino}acetamide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2027
Polymers17,4841
Non-polymers7186
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.394, 60.446, 54.043
Angle α, β, γ (deg.)90.00, 114.67, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 17484.475 Da / Num. of mol.: 1 / Fragment: catalytic domain / Mutation: F171D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Plasmid: Pet 21 / 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-D3X / N-hydroxy-2-{[(4-methoxyphenyl)sulfonyl](2-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}ethyl)amino}acetamide


Mass: 466.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H26N2O11S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.18 Å3/Da / Density % sol: 43.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M TRIS, 30% PEG 6000, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION ENHANCE ULTRA / Wavelength: 1.54056 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Oct 28, 2003 / Details: MIRRORS
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 1.8→30.22 Å / Num. all: 12054 / Num. obs: 12054 / % possible obs: 86.2 % / Redundancy: 3.8 % / Biso Wilson estimate: 10.462 Å2 / Rmerge(I) obs: 0.042 / Rsym value: 0.042 / Net I/σ(I): 12.9
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 1.3 % / Rmerge(I) obs: 0.115 / Mean I/σ(I) obs: 6.4 / Num. unique all: 490 / Rsym value: 0.115 / % possible all: 24.7

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Processing

Software
NameVersionClassification
CrysalisProdata collection
MOLREPphasing
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1Y93

1y93


Resolution: 1.81→30.22 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.907 / SU B: 2.58 / SU ML: 0.08 / Cross valid method: THROUGHOUT / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21899 1066 8.8 %RANDOM
Rwork0.16079 ---
all0.16585 10987 --
obs0.16585 10987 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 11.272 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å2-0.25 Å2
2--0.2 Å20 Å2
3----0.44 Å2
Refinement stepCycle: LAST / Resolution: 1.81→30.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1238 0 36 146 1420
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0211307
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.211.9421775
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9245157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.14723.17563
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.97115188
X-RAY DIFFRACTIONr_dihedral_angle_4_deg5.412157
X-RAY DIFFRACTIONr_chiral_restr0.0860.2184
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021025
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1950.2657
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.2909
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1360.2105
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.070.215
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.210.263
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1660.223
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.741.5791
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.23421242
X-RAY DIFFRACTIONr_scbond_it1.943587
X-RAY DIFFRACTIONr_scangle_it2.9094.5533
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free8.08435
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.81→1.857 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 7 -
Rwork0.174 127 -
obs--100 %

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