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- PDB-3tsk: Human MMP12 in complex with L-glutamate motif inhibitor -

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Basic information

Entry
Database: PDB / ID: 3tsk
TitleHuman MMP12 in complex with L-glutamate motif inhibitor
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / pseudo dipeptides / potent inhibitors / metzincin / Zinc metalloprotease / 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 / response to amyloid-beta / positive regulation of interferon-alpha production / 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 / 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
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
N~2~-{3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}-L-GLUTAMINYL-L-ALPHA-GLUTAMINE / Chem-QEG / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / RIGID BODY REFINEMENT / Resolution: 2 Å
AuthorsStura, E.A. / Dive, V. / Devel, L. / Czarny, B. / Beau, F. / Vera, L.
CitationJournal: J.Biol.Chem. / Year: 2012
Title: Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.
Authors: Devel, L. / Beau, F. / Amoura, M. / Vera, L. / Cassar-Lajeunesse, E. / Garcia, S. / Czarny, B. / Stura, E.A. / Dive, V.
History
DepositionSep 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 17, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Sep 13, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4317
Polymers17,6161
Non-polymers8166
Water3,495194
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.710, 63.060, 37.950
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 17615.670 Da / Num. of mol.: 1 / Fragment: Catalitic subunit (UNP residues 106-263) / Mutation: F171D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HME, MMP12 / 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-QEG / N~2~-{3-[4-(4-phenylthiophen-2-yl)phenyl]propanoyl}-L-glutaminyl-L-alpha-glutamine


Type: Peptide-like / Class: Inhibitor / Mass: 564.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32N4O6S
References: N~2~-{3-[4-(4-PHENYLTHIOPHEN-2-YL)PHENYL]PROPANOYL}-L-GLUTAMINYL-L-ALPHA-GLUTAMINE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 2.37 Å3/Da / Density % sol: 48.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: MMP-12 at 0.4 mM co-crystallized with 100 mM AHA and compound QEG at 1 mM against reservoir solution: 27% PEG 10000, 100 mM Tris-HCl, pH 9.5. 24h in cryoprotectant to remove AHA. 70 MICRO-M ...Details: MMP-12 at 0.4 mM co-crystallized with 100 mM AHA and compound QEG at 1 mM against reservoir solution: 27% PEG 10000, 100 mM Tris-HCl, pH 9.5. 24h in cryoprotectant to remove AHA. 70 MICRO-M compound QEG in 10% di-ethylene glycol, 10% 1.2-propanediol, 10% glycerol, 10% PEG 10K, 200 mM NaCl, 33.3 mM sodium acetate, 33.3 mM ADA, 33.3 mM bicine, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 1, 2011 / Details: bent cylindrical mirror
RadiationMonochromator: horizontally diffracting Si (111) monochromator and Pt coated mirrors in Kirkpatrick-Baez geometry for focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2→33.33 Å / Num. obs: 9572 / % possible obs: 83.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.142 / Rsym value: 0.074 / Net I/σ(I): 7.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
2-2.113.41.0661.60.926180.9
6.32-33.334.40.04520.70.04179.5
4.47-6.324.50.06220.20.056182.5
3.65-4.474.50.0818.30.072184.6
3.16-3.654.30.10612.90.095185.1
2.83-3.163.80.1757.90.154185.6
2.58-2.833.50.35.30.263186.5
2.39-2.583.40.4223.60.369185.4
2.24-2.583.40.6032.70.524183.5
2.11-2.243.40.7872.10.686183.1

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Processing

Software
NameVersionClassification
DNAdata collection
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
REFMAC5.5.0109phasing
RefinementMethod to determine structure: RIGID BODY REFINEMENT
Starting model: 3TS4

3ts4


Resolution: 2→33.331 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.935 / SU B: 5.183 / SU ML: 0.138 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / ESU R: 0.249 / ESU R Free: 0.206 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23174 458 4.8 %RANDOM
Rwork0.16216 ---
obs0.1655 9114 80.74 %-
all-11288 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.721 Å2
Baniso -1Baniso -2Baniso -3
1--1.44 Å20 Å20 Å2
2---0.26 Å20 Å2
3---1.71 Å2
Refinement stepCycle: LAST / Resolution: 2→33.331 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1246 0 45 194 1485
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0211358
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.221.9521852
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5965164
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.63223.18266
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.95215197
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.712158
X-RAY DIFFRACTIONr_chiral_restr0.1770.2186
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211093
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.0171.5800
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.75621283
X-RAY DIFFRACTIONr_scbond_it2.73558
X-RAY DIFFRACTIONr_scangle_it4.1294.5558
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 35 -
Rwork0.232 648 -
obs--80.73 %

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