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- PDB-4i03: Human MMP12 in complex with a PEG-linked bifunctional L-glutamate... -

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Basic information

Entry
Database: PDB / ID: 4i03
TitleHuman MMP12 in complex with a PEG-linked bifunctional L-glutamate motif inhibitor
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / selective carboxylate based MMP-12 bifunctional inhibitor / METZINCIN / Zinc protease / 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 / 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-L88 / DI(HYDROXYETHYL)ETHER / S-1,2-PROPANEDIOL / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsStura, E.A. / Vera, L. / Devel, L. / Cassar-Lajeunesse, E. / Dive, V.
Citation
Journal: J.Struct.Biol. / Year: 2013
Title: Crystallization of bi-functional ligand protein complexes.
Authors: Antoni, C. / Vera, L. / Devel, L. / Catalani, M.P. / Czarny, B. / Cassar-Lajeunesse, E. / Nuti, E. / Rossello, A. / Dive, V. / Stura, E.A.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs.
Authors: Rossello, A. / Nuti, E. / Catalani, M.P. / Carelli, P. / Orlandini, E. / Rapposelli, S. / Tuccinardi, T. / Atkinson, S.J. / Murphy, G. / Balsamo, A.
#2: Journal: To Be Published
History
DepositionNov 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,80719
Polymers17,5581
Non-polymers2,24918
Water3,081171
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.790, 60.100, 54.920
Angle α, β, γ (deg.)90.00, 116.67, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-484-

HOH

DetailsThe bifunctional inhibitor joins two MMP-12 molecules creating a crystallographic dimer

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 17557.633 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 106-263) / Mutation: F171D, E219A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: Escherichia coli / Gene: HME, MMP12 / Plasmid: PET24A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P39900, macrophage elastase

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Non-polymers , 9 types, 189 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-L88 / (4R,22R)-5,21-dioxo-4,22-bis({3-[4-(4-phenylthiophen-2-yl)phenyl]propanoyl}amino)-10,13,16-trioxa-6,20-diazapentacosane-1,25-dioic acid


Mass: 1059.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C58H66N4O11S2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-PGO / S-1,2-PROPANEDIOL


Mass: 76.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#9: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 43.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein solution: 222 microM MMP12 mutant E219A 106 microM bifunctional inhibitor LD884. Reservoir: 27% PEG 10K, 150mM imidazole piperidine, pH 8.5. Cryoprotectant: 5 % di-ethylene glycol + ...Details: Protein solution: 222 microM MMP12 mutant E219A 106 microM bifunctional inhibitor LD884. Reservoir: 27% PEG 10K, 150mM imidazole piperidine, pH 8.5. Cryoprotectant: 5 % di-ethylene glycol + 5 % ethylene glycol + 10 % 1,2-propanediol + 5 % DMSO + 5 % glycerol, 25% MPEG 5K, 100mM (Na acetate, ADA, Bicine 10% pH 4.0/90% pH 9.0), VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.98011 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 12, 2012 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. all: 16789 / Num. obs: 16663 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -4 / Redundancy: 4.14 % / Biso Wilson estimate: 28.35 Å2 / Rmerge(I) obs: 0.102 / Rsym value: 0.089 / Net I/σ(I): 9.52
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.7-1.84.020.8871.7126930.76897.2
1.8-1.924.120.523.0625400.45199.7
1.92-2.084.190.2985.1823720.25999.6
2.08-2.274.170.1987.3421510.172100
2.27-2.544.260.14310.0219830.12599.7
2.54-2.934.240.09713.9517480.08499.5
2.93-3.594.230.06919.5914800.0699.5
3.59-5.074.030.05324.7511640.04699.3
5.07-503.990.05525.836580.04899.2

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Processing

Software
NameVersionClassification
DNAdata collection
MOLREPphasing
REFMAC5.5.0109refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→36.67 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.96 / SU B: 2.294 / SU ML: 0.074 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -4 / ESU R: 0.104 / ESU R Free: 0.108 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19397 834 5 %RANDOM
Rwork0.14361 ---
obs0.14626 15828 100 %-
all-16663 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.56 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20.06 Å2
2---0.05 Å20 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.7→36.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 139 171 1552
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0211501
X-RAY DIFFRACTIONr_bond_other_d0.0020.021045
X-RAY DIFFRACTIONr_angle_refined_deg2.0381.9992015
X-RAY DIFFRACTIONr_angle_other_deg1.03332515
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0555176
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.84222.87966
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.63415215
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.651159
X-RAY DIFFRACTIONr_chiral_restr0.1140.2197
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021673
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02343
X-RAY DIFFRACTIONr_mcbond_it1.3721.5836
X-RAY DIFFRACTIONr_mcbond_other0.4141.5347
X-RAY DIFFRACTIONr_mcangle_it2.2921349
X-RAY DIFFRACTIONr_scbond_it3.1313665
X-RAY DIFFRACTIONr_scangle_it4.8654.5664
LS refinement shellResolution: 1.696→1.74 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 60 -
Rwork0.252 1124 -
obs--100 %

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