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- PDB-4xct: Crystal structure of a hydroxamate based inhibitor ARP101 (EN73) ... -

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Basic information

Entry
Database: PDB / ID: 4xct
TitleCrystal structure of a hydroxamate based inhibitor ARP101 (EN73) in complex with the MMP-9 catalytic domain.
ComponentsMatrix metalloproteinase-9,Matrix metalloproteinase-9
KeywordsHYDROLASE / Inhibitor-complex / metalloprotease
Function / homology
Function and homology information


gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / cellular response to UV-A / regulation of neuroinflammatory response / positive regulation of keratinocyte migration / Assembly of collagen fibrils and other multimeric structures / positive regulation of DNA binding / positive regulation of epidermal growth factor receptor signaling pathway / Activation of Matrix Metalloproteinases ...gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / cellular response to UV-A / regulation of neuroinflammatory response / positive regulation of keratinocyte migration / Assembly of collagen fibrils and other multimeric structures / positive regulation of DNA binding / positive regulation of epidermal growth factor receptor signaling pathway / Activation of Matrix Metalloproteinases / endodermal cell differentiation / negative regulation of intrinsic apoptotic signaling pathway / positive regulation of release of cytochrome c from mitochondria / response to amyloid-beta / Collagen degradation / collagen catabolic process / macrophage differentiation / EPH-ephrin mediated repulsion of cells / extracellular matrix disassembly / ephrin receptor signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / collagen binding / Degradation of the extracellular matrix / extracellular matrix organization / embryo implantation / positive regulation of receptor binding / skeletal system development / Signaling by SCF-KIT / metalloendopeptidase activity / metallopeptidase activity / tertiary granule lumen / positive regulation of protein phosphorylation / cell migration / peptidase activity / cellular response to lipopolysaccharide / : / Interleukin-4 and Interleukin-13 signaling / endopeptidase activity / ficolin-1-rich granule lumen / Extra-nuclear estrogen signaling / positive regulation of apoptotic process / serine-type endopeptidase activity / apoptotic process / Neutrophil degranulation / negative regulation of apoptotic process / proteolysis / extracellular space / extracellular exosome / extracellular region / zinc ion binding / 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
(2S,3S)-butane-2,3-diol / Chem-N73 / S-1,2-PROPANEDIOL / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsStura, E.A. / Tepshi, L. / Nuti, E. / Dive, V. / Cassar-Lajeunesse, E. / Vera, L. / 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
DepositionDec 18, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2015Group: Database references
Revision 1.2Oct 7, 2015Group: Database references
Revision 2.0May 29, 2019Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / pdbx_distant_solvent_atoms / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_solvent_atom_site_mapping / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / struct_conn / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_seq_id / _atom_site.label_alt_id / _atom_site.occupancy / _atom_site.pdbx_auth_seq_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.id / _atom_site_anisotrop.pdbx_PDB_residue_no / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_alt_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_distant_solvent_atoms.auth_seq_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_solvent_atom_site_mapping.auth_seq_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_special_symmetry.auth_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1Jan 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,96617
Polymers17,5721
Non-polymers1,39416
Water4,143230
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-6 kcal/mol
Surface area8150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.600, 39.600, 163.960
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-494-

HOH

21A-611-

HOH

31A-627-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 17571.518 Da / Num. of mol.: 1 / Fragment: UNP residues 113-216,UNP residues 392-444
Source method: isolated from a genetically manipulated source
Details: N73 zinc chelating inhibitor - human wild-type MMP-9 catalytic domain unp residues 107-215/391-443
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP9, CLG4B / Plasmid: pET-14b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): star / References: UniProt: P14780, gelatinase B

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Non-polymers , 9 types, 246 molecules

#2: Chemical ChemComp-N73 / (2~{R})-3-methyl-~{N}-oxidanylidene-2-[(4-phenylphenyl)sulfonyl-propan-2-yloxy-amino]butanamide


Mass: 404.480 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C20H24N2O5S
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 76.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2
#9: Chemical ChemComp-BUD / (2S,3S)-butane-2,3-diol


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.07 Å3/Da / Density % sol: 40.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: protein: hMMP-9-WT at 337 micro-M with 120 milli-M acetohydroxamic acid. precipitant: 40.5% MPEG 5,000, 180 mM imidazole piperidine, pH 8.5. Cryoprotectant: 40% CryoProtX-C1, 10% PEG 10K, 10% PCTP 50/50
PH range: 7.0-8.5 / Temp details: constant incubator

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 16, 2014 / Details: mirrors
RadiationMonochromator: Channel cut Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.3→52 Å / Num. all: 38096 / Num. obs: 38007 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.2 % / Rmerge(I) obs: 0.06 / Rsym value: 0.055 / Net I/σ(I): 14.62
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 6.16 % / Rmerge(I) obs: 1.392 / Mean I/σ(I) obs: 1.12 / % possible all: 99.1

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Processing

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

4h3x


Resolution: 1.3→34.295 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 32.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.231 1892 4.99 %Random selection
Rwork0.1668 ---
obs0.1701 37897 99.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.3→34.295 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1277 0 51 230 1558
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061497
X-RAY DIFFRACTIONf_angle_d1.0492047
X-RAY DIFFRACTIONf_dihedral_angle_d14.462548
X-RAY DIFFRACTIONf_chiral_restr0.053198
X-RAY DIFFRACTIONf_plane_restr0.005273
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2996-1.33210.32031310.2762473X-RAY DIFFRACTION98
1.3321-1.36810.31981340.27232564X-RAY DIFFRACTION100
1.3681-1.40840.32881310.26312504X-RAY DIFFRACTION100
1.4084-1.45390.33491330.25022525X-RAY DIFFRACTION100
1.4539-1.50580.33371300.22582506X-RAY DIFFRACTION100
1.5058-1.56610.27351350.20852572X-RAY DIFFRACTION100
1.5661-1.63740.27681340.18562536X-RAY DIFFRACTION100
1.6374-1.72370.22841350.17462574X-RAY DIFFRACTION100
1.7237-1.83170.25181330.16532523X-RAY DIFFRACTION100
1.8317-1.97310.22841370.15832589X-RAY DIFFRACTION100
1.9731-2.17160.20571350.15292564X-RAY DIFFRACTION100
2.1716-2.48580.22191380.15752627X-RAY DIFFRACTION100
2.4858-3.13150.22441380.1682645X-RAY DIFFRACTION100
3.1315-34.30650.20631480.14432803X-RAY DIFFRACTION100

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