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- PDB-4hma: Crystal structure of an MMP twin carboxylate based inhibitor LC20... -

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Basic information

Entry
Database: PDB / ID: 4hma
TitleCrystal structure of an MMP twin carboxylate based inhibitor LC20 in complex with the MMP-9 catalytic domain
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 / : / : / 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 ...gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / : / : / 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 / negative regulation of intrinsic apoptotic signaling pathway / positive regulation of release of cytochrome c from mitochondria / endodermal cell differentiation / response to amyloid-beta / Collagen degradation / collagen catabolic process / macrophage differentiation / extracellular matrix disassembly / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / collagen binding / positive regulation of vascular associated smooth muscle cell proliferation / Degradation of the extracellular matrix / extracellular matrix organization / embryo implantation / skeletal system development / Signaling by SCF-KIT / metalloendopeptidase activity / positive regulation of protein phosphorylation / metallopeptidase activity / tertiary granule lumen / 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
Chem-0ZD / D-MALATE / DI(HYDROXYETHYL)ETHER / S-1,2-PROPANEDIOL / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsStura, E.A. / Antoni, C. / Vera, L. / Nuti, E. / Carafa, L. / Cassar-Lajeunesse, 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
DepositionOct 18, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1May 1, 2013Group: Database references
Revision 1.2Oct 8, 2014Group: Structure summary
Revision 1.3Aug 12, 2015Group: Database references
Revision 1.4Aug 9, 2017Group: Data collection / Refinement description / Source and taxonomy
Category: diffrn_detector / entity_src_gen / software / Item: _diffrn_detector.detector
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_alt_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_alt_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.pdbx_ptnr1_label_alt_id / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,04532
Polymers35,8662
Non-polymers3,17930
Water6,215345
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4570 Å2
ΔGint-76 kcal/mol
Surface area17170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.870, 98.240, 47.440
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
DetailsTHE TWIN INHIBITOR 0Z CAUSE THE ENZYME TO FORM A DIMER

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Components

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Protein , 1 types, 2 molecules AB

#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.: 2 / Fragment: MMP-9 catalytic domain 107-215,391-443 / 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, 375 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-0ZD / N,N'-bis(2-[(biphenyl-4ylsulfonyl)[(2R)-1-hydroxy-3-methyl-1-oxobutan-2-yl]-amino]ethyl)benzene-1,3-dicarboxamide


Mass: 883.040 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H50N4O10S2
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-PGO / S-1,2-PROPANEDIOL


Mass: 76.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O2
#7: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-MLT / D-MALATE / (2R)-2-HYDROXYBUTANEDIOIC ACID / 2-HYDROXY-SUCCINIC ACID


Mass: 134.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O5
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / 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: 48.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: Protein: human MMP9 (E402Q) at 308.7 micro-M twin inhibitor LC20 at 154 micro-M (stoichiometry 2:1) and 120mM acetohydroxamic acid. RESERVOIR: 12% Polyethylene glycol 20,000, 1.5M NaCl, 0.1 ...Details: Protein: human MMP9 (E402Q) at 308.7 micro-M twin inhibitor LC20 at 154 micro-M (stoichiometry 2:1) and 120mM acetohydroxamic acid. RESERVOIR: 12% Polyethylene glycol 20,000, 1.5M NaCl, 0.1 M PCTP (Na propionate, Na cacodylate, Bis-Tris-propane ratio 2:1:2; 75% pH 4, 25% pH 9.5) CRYOPROTECTANT: 40% C2 (25 % di-ethylene glycol + 25 % glycerol + 25 % 1,2-propanediol), 9% PEG 10,000 1.5M NaCl, 0.1M PCTP 80/2, 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: bent cylindrical mirror
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 1.94→50 Å / Num. all: 26173 / Num. obs: 26019 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.98 % / Biso Wilson estimate: 36.556 Å2 / Rmerge(I) obs: 0.166 / Rsym value: 0.155 / Net I/σ(I): 8.19
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.94-2.067.871.5331.341621.43296.6
2.06-2.28.010.962.2438910.89899.9
2.2-2.388.220.6743.2936750.632100
2.38-2.68.210.4294.9433570.402100
2.6-2.918.10.2498.0230680.233100
2.91-3.368.050.14312.5827400.134100
3.36-4.117.760.08718.9523420.08199.9
4.11-5.797.620.06822.7518370.064100
5.79-507.150.05623.2111010.05299.5

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Processing

Software
NameVersionClassification
DNAdata collection
MOLREPphasing
REFMAC5.5.0109refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H82

4h82


Resolution: 1.94→42.72 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.94 / SU B: 5.156 / SU ML: 0.145 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -3 / ESU R: 0.212 / ESU R Free: 0.199 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28302 1301 5 %RANDOM
Rwork0.21088 ---
obs0.21439 24713 100 %-
all-26019 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.048 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å20 Å2
2---0.65 Å20 Å2
3----0.18 Å2
Refinement stepCycle: LAST / Resolution: 1.94→42.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2550 0 190 345 3085
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0212871
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9661.9733886
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.745331
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.33623.611144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.53115371
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.0171512
X-RAY DIFFRACTIONr_chiral_restr0.1580.2374
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212296
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_it1.2411.51627
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.1222599
X-RAY DIFFRACTIONr_scbond_it3.11431244
X-RAY DIFFRACTIONr_scangle_it4.5724.51287
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.943→1.993 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.373 88 -
Rwork0.32 1674 -
obs--100 %

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