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- PDB-4wzv: Crystal structure of a hydroxamate based inhibitor EN140 in compl... -

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Basic information

Entry
Database: PDB / ID: 4wzv
TitleCrystal structure of a hydroxamate based inhibitor EN140 in complex with the MMP-9 catalytic domain
ComponentsMatrix metalloproteinase-9,Matrix metalloproteinase-9
KeywordsHYDROLASE / MMP9 Inhibitor complex / Thyroid hormone-binding protein
Function / homology
Function and homology information


gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / cellular response to UV-A / positive regulation of keratinocyte migration / regulation of neuroinflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / Assembly of collagen fibrils and other multimeric structures / positive regulation of DNA binding ...gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / cellular response to UV-A / positive regulation of keratinocyte migration / regulation of neuroinflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / Assembly of collagen fibrils and other multimeric structures / positive regulation of DNA binding / Activation of Matrix Metalloproteinases / endodermal cell differentiation / positive regulation of release of cytochrome c from mitochondria / response to amyloid-beta / macrophage differentiation / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / collagen binding / cellular response to cadmium ion / embryo implantation / Degradation of the extracellular matrix / extracellular matrix organization / positive regulation of receptor binding / skeletal system development / Signaling by SCF-KIT / metalloendopeptidase activity / cellular response to reactive oxygen species / metallopeptidase activity / cell migration / tertiary granule lumen / peptidase activity / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / collagen-containing extracellular matrix / endopeptidase activity / ficolin-1-rich granule lumen / Extra-nuclear estrogen signaling / positive regulation of protein phosphorylation / positive regulation of apoptotic process / serine-type endopeptidase activity / Neutrophil degranulation / negative regulation of apoptotic process / apoptotic process / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region / identical protein binding
Similarity search - Function
Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site ...Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / 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 / Kringle-like fold / Neutral zinc metallopeptidases, zinc-binding region signature. / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
AZIDE ION / Chem-E40 / DI(HYDROXYETHYL)ETHER / S-1,2-PROPANEDIOL / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsStura, E.A. / Vera, L. / Cassar-Lajeunesse, E. / Nuti, E. / Dive, V. / Rossello, A.
CitationJournal: J.Med.Chem. / Year: 2015
Title: N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity.
Authors: Nuti, E. / Cantelmo, A.R. / Gallo, C. / Bruno, A. / Bassani, B. / Camodeca, C. / Tuccinardi, T. / Vera, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Martinelli, A. / Dive, V. / Albini, A. / Rossello, A.
History
DepositionNov 20, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2015Group: Database references
Revision 1.2Jan 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 / diffrn_radiation_wavelength / 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.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_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: Matrix metalloproteinase-9,Matrix metalloproteinase-9
B: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,44331
Polymers35,8102
Non-polymers2,63329
Water11,349630
1
A: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,15012
Polymers17,9051
Non-polymers1,24511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,29319
Polymers17,9051
Non-polymers1,38818
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.950, 97.390, 45.670
Angle α, β, γ (deg.)90.00, 112.72, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Matrix metalloproteinase-9,Matrix metalloproteinase-9 / MMP-9 / 92 kDa gelatinase / 92 kDa type IV collagenase / Gelatinase B / GELB


Mass: 17904.859 Da / Num. of mol.: 2
Fragment: catalytic domain, UNP residues 110-216,catalytic domain, UNP residues 392-444
Source method: isolated from a genetically manipulated source
Details: E40 is a ligand. 7 residues have been cleaved. unp residues 110-214 and 391-444
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP9, CLG4B / Production host: Escherichia coli (E. coli) / References: UniProt: P14780, gelatinase B

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Non-polymers , 10 types, 659 molecules

#2: Chemical ChemComp-E40 / (2R)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-2-{[(4'-methoxybiphenyl-4-yl)sulfonyl](propan-2-yloxy)amino}butanamide / EN140


Mass: 567.610 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C28H29N3O8S / Source: (gene. exp.) Homo sapiens (human) / Gene: CLG4B / Production host: Escherichia coli (E. coli)
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-AZI / AZIDE ION


Mass: 42.020 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: N3
#9: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Na
#10: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 630 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.31 % / Description: long prismatic crystals
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.25
Details: protein: 5mg/mL hMMP9-WT with 120 milli-M acetohydroxamic acid. Reservoir: 36% MPEG 5K, 90mM bicine, pH 7.25. Cryoprotectant: 40% MPEG 5K, 5% Di-ethyleneglycol, 10% AAB buffer, pH 8.0
PH range: 7.25-8.0 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Nov 24, 2010 / Details: mirrors
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. all: 38771 / Num. obs: 38365 / % possible obs: 99 % / Redundancy: 4.17 % / Biso Wilson estimate: 21.971 Å2 / Rmerge(I) obs: 0.166 / Rsym value: 0.144 / Net I/σ(I): 8.41
Reflection shellResolution: 1.65→1.75 Å / Redundancy: 3.92 % / Rmerge(I) obs: 1.339 / Mean I/σ(I) obs: 1.19 / % possible all: 94.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H3X

4h3x


Resolution: 1.65→42.126 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 20.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2295 1918 5 %Random selection
Rwork0.176 ---
obs0.1787 38347 99.14 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.65→42.126 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2586 0 72 630 3288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072867
X-RAY DIFFRACTIONf_angle_d1.1113910
X-RAY DIFFRACTIONf_dihedral_angle_d16.4251050
X-RAY DIFFRACTIONf_chiral_restr0.044373
X-RAY DIFFRACTIONf_plane_restr0.008512
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6503-1.69160.25281230.18822350X-RAY DIFFRACTION90
1.6916-1.73730.20731380.15792609X-RAY DIFFRACTION99
1.7373-1.78840.26031360.16682599X-RAY DIFFRACTION100
1.7884-1.84610.21351380.15922605X-RAY DIFFRACTION100
1.8461-1.91210.20351390.15842640X-RAY DIFFRACTION100
1.9121-1.98870.18951380.15022636X-RAY DIFFRACTION100
1.9887-2.07920.25681360.16562583X-RAY DIFFRACTION100
2.0792-2.18880.22271370.16462597X-RAY DIFFRACTION100
2.1888-2.32590.20891380.16012613X-RAY DIFFRACTION100
2.3259-2.50550.22321400.18062656X-RAY DIFFRACTION100
2.5055-2.75760.21411370.17492603X-RAY DIFFRACTION100
2.7576-3.15650.23041380.18312638X-RAY DIFFRACTION100
3.1565-3.97640.2331390.16962638X-RAY DIFFRACTION100
3.9764-42.13990.25271410.20982662X-RAY DIFFRACTION100

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