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- PDB-5i4o: Crystal structure of the catalytic domain of MMP-12 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5i4o
TitleCrystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated triazole-linked carboxylate zinc-chelator water-soluble inhibitor (DC28).
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 / 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-V28 / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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 12, 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 1.3Jan 24, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id ..._entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain / _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_asym_id / _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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.ptnr3_symmetry / _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.ptnr1_symmetry / _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 / _struct_conn.ptnr2_symmetry

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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)73,93428
Polymers70,4594
Non-polymers3,47524
Water8,395466
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4837
Polymers17,6151
Non-polymers8696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4837
Polymers17,6151
Non-polymers8696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4837
Polymers17,6151
Non-polymers8696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4837
Polymers17,6151
Non-polymers8696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.980, 63.510, 78.640
Angle α, β, γ (deg.)90.00, 102.31, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 17614.684 Da / Num. of mol.: 4 / Fragment: UNP residues 106-238 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Details: Catalytic domain of human macrophage elastase (MMP-12)
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: P39900, macrophage elastase
#2: Chemical
ChemComp-V28 / N-({1-[2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl]-1H-1,2,3-triazol-4-yl}methyl)-N-[([1,1'-biphenyl]-4-yl)sulfonyl]-D-valine


Mass: 617.671 Da / Num. of mol.: 4 / Mutation: F171D, E219Q
Source method: isolated from a genetically manipulated source
Formula: C28H35N5O9S
Details: Catalytic domain of human macrophage elastase (MMP-12)
Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / 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: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 466 / 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: 2.22 Å3/Da / Density % sol: 44.54 % / Description: small thin plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein-ligand: 465 micro-M hMMP12 F171D E219Q, 0.020 M acetohydroxamic acid, 10% DMSO, 0.5 milli-M inhibitor (DC28). Precipitant: 40.5% PEG4K, 10% dioxane, 2% ethylene glycol, 0.18 M ...Details: Protein-ligand: 465 micro-M hMMP12 F171D E219Q, 0.020 M acetohydroxamic acid, 10% DMSO, 0.5 milli-M inhibitor (DC28). Precipitant: 40.5% PEG4K, 10% dioxane, 2% ethylene glycol, 0.18 M imidazole piperidine, pH 8.5. Cryoprotectant:40% cryomix CM12: (,25 % diethylene glycol + 12.5 % glycerol + 25 % 1,2-propanediol + 12.5 % 1,4-dioxane), 25% PEG 6K, 0.1 M TRIS HCl, pH 8.0.
PH range: 8-8.5 / 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 2 / Wavelength: 0.9801 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 24, 2014 / Details: mirrors
RadiationMonochromator: Cryogenically cooled channel cut Si[111] crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.95→44.56 Å / Num. obs: 45133 / % possible obs: 98.4 % / Observed criterion σ(I): -3 / Redundancy: 4.49 % / Biso Wilson estimate: 24.46 Å2 / Rmerge(I) obs: 0.23 / Rsym value: 0.21 / Net I/σ(I): 4.79
Reflection shellResolution: 1.95→2 Å / Redundancy: 4.25 % / Rmerge(I) obs: 0.985 / Mean I/σ(I) obs: 1.68 / % possible all: 86.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IOL

5iol


Resolution: 2.05→32.87 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.911 / SU B: 5.127 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R: 0.278 / ESU R Free: 0.204 / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1917 5 %RANDOM
Rwork0.21 ---
obs0.212 36421 98.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å20 Å20.16 Å2
2---0.24 Å20 Å2
3---0.32 Å2
Refinement stepCycle: LAST / Resolution: 2.05→32.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5080 0 20 466 5566
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0195256
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9381.9517149
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.895624
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.18623.202253
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.28415758
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.2411528
X-RAY DIFFRACTIONr_chiral_restr0.1590.2742
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0214144
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_it3.052.7442502
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.3444.0913124
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.8333.1412754
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.27424.4768559
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.1 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 141 -
Rwork0.265 2675 -
obs--98.29 %

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