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- PDB-4h82: Crystal structure of mutant MMP-9 catalytic domain in complex wit... -

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Basic information

Entry
Database: PDB / ID: 4h82
TitleCrystal structure of mutant MMP-9 catalytic domain in complex with a twin inhibitor.
ComponentsMatrix metalloproteinase-9
Keywordshydrolase/hydrolase inhibitor / HYDROLASE/TWIN INHIBITOR / Zincin-like / Gelatinase / Collagenase (Catalytic Domain) / hydrolase-hydrolase inhibitor complex
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 / endodermal cell differentiation ...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 / endodermal cell differentiation / Activation of Matrix Metalloproteinases / positive regulation of release of cytochrome c from mitochondria / response to amyloid-beta / macrophage differentiation / Collagen degradation / EPH-ephrin mediated repulsion of cells / collagen catabolic process / extracellular matrix disassembly / ephrin receptor signaling pathway / positive regulation of DNA binding / negative regulation of intrinsic apoptotic signaling pathway / embryo implantation / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to cadmium ion / collagen binding / 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 / collagen-containing extracellular matrix / Interleukin-4 and Interleukin-13 signaling / endopeptidase activity / cellular response to lipopolysaccharide / ficolin-1-rich granule lumen / Extra-nuclear estrogen signaling / positive regulation of protein phosphorylation / positive regulation of apoptotic process / serine-type endopeptidase activity / apoptotic process / Neutrophil degranulation / negative regulation of 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
Chem-L29 / DI(HYDROXYETHYL)ETHER / S-1,2-PROPANEDIOL / PROPANOIC ACID / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsAntoni, C. / Stura, E.A. / Vera, L. / Cassar-Lajeunesse, E. / Nuti, E. / Dive, V. / Rossello, A.
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.
History
DepositionSep 21, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Oct 15, 2014Group: Derived calculations
Revision 1.3Aug 12, 2015Group: Database references
Revision 1.4Aug 9, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.5Sep 20, 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_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.ptnr2_auth_asym_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_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.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.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_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: Matrix metalloproteinase-9
B: Matrix metalloproteinase-9
C: Matrix metalloproteinase-9
D: Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,69938
Polymers71,7314
Non-polymers3,96834
Water12,683704
1
A: Matrix metalloproteinase-9
B: Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,28113
Polymers35,8662
Non-polymers1,41511
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-89 kcal/mol
Surface area15700 Å2
MethodPISA
2
C: Matrix metalloproteinase-9
D: Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,41825
Polymers35,8662
Non-polymers2,55223
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3150 Å2
ΔGint-83 kcal/mol
Surface area16600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.900, 98.860, 47.130
Angle α, β, γ (deg.)90.03, 111.95, 89.98
Int Tables number1
Space group name H-MP1
DetailsThe assembly in the asymetric unit are two dimers. Its biological significance is debatable.

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Matrix metalloproteinase-9 / / MMP-9 / 92 kDa gelatinase / 92 kDa type IV collagenase / Gelatinase B / GELB / 67 kDa matrix ...MMP-9 / 92 kDa gelatinase / 92 kDa type IV collagenase / Gelatinase B / GELB / 67 kDa matrix metalloproteinase-9 / 82 kDa matrix metalloproteinase-9


Mass: 17932.871 Da / Num. of mol.: 4 / Fragment: MMP-9 catalytic domain 107-215,391-444 / Mutation: V391Q E402Q
Source method: isolated from a genetically manipulated source
Details: construct: 110 216 and 392 444 Mutagenesis: Glu402Gln Structure: renumbered omi tting missing domain.
Source: (gene. exp.) Homo sapiens (human) / Gene: CLG4B, MMP9 / Plasmid: pET-14b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3 star) / References: UniProt: P14780, gelatinase B

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Non-polymers , 8 types, 738 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-L29 / N,N'-bis(2-{(biphenyl-4-ylsulfonyl)[(2R)-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]amino}ethyl)benzene-1,3-dicarboxamide (non-preferred name)


Mass: 913.069 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C46H52N6O10S2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-PPI / PROPANOIC ACID / Propionic acid


Mass: 74.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O2
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 76.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O2
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 704 / 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: 2.4 Å3/Da / Density % sol: 48.83 %
Crystal growTemperature: 293 K / pH: 8
Details: Protein: MMP9h Nter=GFQT E402Q V391Q at 384.3 micro-M with 120 milli-M AHA Reservoir: 10% MPEG 20K, 100mM PCTP 75/25, 1.5 NaCl. Cryoprotectant: 12.5% di-ethylene glycol, 12.5% DMSO, 12.5% ...Details: Protein: MMP9h Nter=GFQT E402Q V391Q at 384.3 micro-M with 120 milli-M AHA Reservoir: 10% MPEG 20K, 100mM PCTP 75/25, 1.5 NaCl. Cryoprotectant: 12.5% di-ethylene glycol, 12.5% DMSO, 12.5% MPD, 12.5% 1,2-propnaediol, 25% glycerol, 9% PEG 10K, 100 milli-M PCTP 80/20, 1.5 NaCl , pH 8.0, 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
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 4, 2012 / Details: MIRRORS
RadiationMonochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
Reflection twinOperator: -h,k,-l / Fraction: 0.48
ReflectionResolution: 1.9→50 Å / Num. obs: 45622 / % possible obs: 86.8 % / Observed criterion σ(I): -3 / Redundancy: 2.25 % / Biso Wilson estimate: 29.73 Å2 / Rmerge(I) obs: 0.132 / Rsym value: 0.104 / Net I/σ(I): 6.35
Reflection shellResolution: 1.9→2.02 Å / Redundancy: 2.17 % / Rmerge(I) obs: 0.773 / Mean I/σ(I) obs: 1.21 / Rsym value: 0.694 / % possible all: 68.6

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Processing

Software
NameVersionClassification
DNAdata collection
MOLREPphasing
PHENIX(phenix.refine: 1.8_1069)refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H1Q

4h1q


Resolution: 1.9→33.46 Å / Isotropic thermal model: Isotropic / σ(F): 1.99 / Phase error: 24.84 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.241 2512 5.51 %
Rwork0.207 --
obs0.209 45613 87 %
all-45622 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.98 Å2
Refinement stepCycle: LAST / Resolution: 1.9→33.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5100 0 223 704 6027
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085626
X-RAY DIFFRACTIONf_angle_d1.2337661
X-RAY DIFFRACTIONf_dihedral_angle_d18.1832059
X-RAY DIFFRACTIONf_chiral_restr0.081729
X-RAY DIFFRACTIONf_plane_restr0.0151013
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9031-1.94450.2961020.27241922X-RAY DIFFRACTION59
1.9445-1.98970.28321190.26182274X-RAY DIFFRACTION69
1.9897-2.03940.24671230.24292331X-RAY DIFFRACTION72
2.0394-2.09460.29761300.24232465X-RAY DIFFRACTION75
2.0946-2.15620.291340.23422544X-RAY DIFFRACTION79
2.1562-2.22580.29241460.22922774X-RAY DIFFRACTION83
2.2258-2.30530.271450.22842763X-RAY DIFFRACTION85
2.3053-2.39760.26541520.22012894X-RAY DIFFRACTION88
2.3976-2.50670.32441530.23372894X-RAY DIFFRACTION89
2.5067-2.63880.26791540.23522939X-RAY DIFFRACTION90
2.6388-2.8040.2341560.21672966X-RAY DIFFRACTION91
2.804-3.02040.28351530.21122900X-RAY DIFFRACTION88
3.0204-3.32410.21611540.18812929X-RAY DIFFRACTION89
3.3241-3.80450.19731520.17252891X-RAY DIFFRACTION88
3.8045-4.7910.18051520.16452889X-RAY DIFFRACTION89
4.791-33.46160.22681560.20982945X-RAY DIFFRACTION90

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