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- PDB-6esm: Crystal structure of MMP9 in complex with inhibitor BE4. -

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Basic information

Entry
Database: PDB / ID: 6esm
TitleCrystal structure of MMP9 in complex with inhibitor BE4.
ComponentsMatrix metalloproteinase-9,Matrix metalloproteinase-9
KeywordsHYDROLASE / metzincin / carboxylate inhibitor alternative zinc-binding groups
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 / collagen catabolic process / EPH-ephrin mediated repulsion of cells / extracellular matrix disassembly / ephrin receptor signaling pathway / positive regulation of DNA binding / negative regulation of intrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to cadmium ion / collagen binding / 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 / Interleukin-4 and Interleukin-13 signaling / collagen-containing extracellular matrix / 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-B9Z / piperazine / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.104 Å
AuthorsCiccone, L. / Tepshi, L. / Nuti, E. / Rossello, A. / Stura, E.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.
Authors: Nuti, E. / Cuffaro, D. / Bernardini, E. / Camodeca, C. / Panelli, L. / Chaves, S. / Ciccone, L. / Tepshi, L. / Vera, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Santos, M.A. / Dive, V. / Rossello, A.
History
DepositionOct 23, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 2.0Jun 6, 2018Group: Atomic model / Data collection / Database references / Category: atom_site / citation
Item: _atom_site.occupancy / _citation.journal_volume ..._atom_site.occupancy / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 2.1Jan 17, 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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)18,6648
Polymers17,9041
Non-polymers7607
Water4,702261
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: see: DOI: 10.1042/BJ20140418
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-24 kcal/mol
Surface area7750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.690, 39.690, 163.660
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-430-

HOH

21A-500-

HOH

31A-609-

HOH

41A-624-

HOH

51A-658-

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: 17903.875 Da / Num. of mol.: 1 / Mutation: E227Q,E227Q
Source method: isolated from a genetically manipulated source
Details: Catalytic domain of MMP-9 without the fibronectin domains.
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 , 5 types, 268 molecules

#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-B9Z / (2~{S})-2-[2-[4-(4-methoxyphenyl)phenyl]sulfanylphenyl]pentanedioic acid


Mass: 422.493 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PZE / piperazine / Piperazine


Mass: 86.136 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10N2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.08 Å3/Da / Density % sol: 40.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein: human MMP9 E402Q 300 micro-M Precipitant: 31.5% MPEG 5K; .14 M imidazole piperidine; pH 8.5 Cryoprotectant: 40% CM2 (25% di-ethylene glycol + 25% glycerol + 25% 1,2-propanediol), ...Details: Protein: human MMP9 E402Q 300 micro-M Precipitant: 31.5% MPEG 5K; .14 M imidazole piperidine; pH 8.5 Cryoprotectant: 40% CM2 (25% di-ethylene glycol + 25% glycerol + 25% 1,2-propanediol), 10% PEG 10K, 200 milli-M NaCl, 100milli-M PCTP 50/50
PH range: 7.0-8.5 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryostream
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.738001 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 8, 2016 / Details: mirrors
RadiationMonochromator: channel cut cryogenically cooled Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.738001 Å / Relative weight: 1
ReflectionResolution: 1.1→54.55 Å / Num. all: 1190339 / Num. obs: 114471 / % possible obs: 98 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 10.4 % / CC1/2: 0.998 / Rpim(I) all: 0.155 / Rsym value: 0.147 / Net I/σ(I): 9.35
Reflection shellResolution: 1.1→1.17 Å / Redundancy: 10.4 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 172046 / CC1/2: 0.624 / Rrim(I) all: 1.25 / Rsym value: 1.19 / % possible all: 87.5

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I12

5i12


Resolution: 1.104→31.69 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.26 / Phase error: 17.39
RfactorNum. reflection% reflectionSelection details
Rfree0.1722 5704 4.98 %RANDOM
Rwork0.1557 ---
obs0.1566 114452 98.88 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.104→31.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1253 0 41 261 1555
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041395
X-RAY DIFFRACTIONf_angle_d0.8021905
X-RAY DIFFRACTIONf_dihedral_angle_d16.761484
X-RAY DIFFRACTIONf_chiral_restr0.077185
X-RAY DIFFRACTIONf_plane_restr0.006252
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1041-1.11670.43911240.32792385X-RAY DIFFRACTION66
1.1167-1.12980.36891910.28183719X-RAY DIFFRACTION100
1.1298-1.14360.26331920.26453637X-RAY DIFFRACTION100
1.1436-1.15810.26331880.25243595X-RAY DIFFRACTION100
1.1581-1.17330.23031980.24163738X-RAY DIFFRACTION100
1.1733-1.18940.25381910.2443615X-RAY DIFFRACTION100
1.1894-1.20640.25091920.23343742X-RAY DIFFRACTION100
1.2064-1.22440.26441850.24543584X-RAY DIFFRACTION100
1.2244-1.24350.27241980.25993748X-RAY DIFFRACTION100
1.2435-1.26390.2411930.24073608X-RAY DIFFRACTION100
1.2639-1.28570.21591960.21273688X-RAY DIFFRACTION100
1.2857-1.30910.23511930.20483638X-RAY DIFFRACTION100
1.3091-1.33430.21111960.18143666X-RAY DIFFRACTION100
1.3343-1.36150.20041930.17583703X-RAY DIFFRACTION100
1.3615-1.39110.22171880.16813602X-RAY DIFFRACTION100
1.3911-1.42350.19821950.15213722X-RAY DIFFRACTION100
1.4235-1.45910.16211960.14123696X-RAY DIFFRACTION100
1.4591-1.49850.16051870.13733617X-RAY DIFFRACTION100
1.4985-1.54260.16161920.13463689X-RAY DIFFRACTION100
1.5426-1.59240.14181940.13083694X-RAY DIFFRACTION100
1.5924-1.64930.1471910.12943673X-RAY DIFFRACTION100
1.6493-1.71530.16031910.12743661X-RAY DIFFRACTION100
1.7153-1.79340.15971970.12793642X-RAY DIFFRACTION100
1.7934-1.88790.13351950.12383684X-RAY DIFFRACTION100
1.8879-2.00620.15581910.12773647X-RAY DIFFRACTION100
2.0062-2.16110.15321890.12733667X-RAY DIFFRACTION100
2.1611-2.37850.13641940.13333662X-RAY DIFFRACTION100
2.3785-2.72250.14431930.14583657X-RAY DIFFRACTION100
2.7225-3.42940.14321910.14353682X-RAY DIFFRACTION100
3.4294-31.70340.15231900.14313687X-RAY DIFFRACTION100

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