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- PDB-3cki: Crystal structure of the TACE-N-TIMP-3 complex -

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Basic information

Entry
Database: PDB / ID: 3cki
TitleCrystal structure of the TACE-N-TIMP-3 complex
Components
  • ADAM 17
  • Metalloproteinase inhibitor 3
KeywordsHydrolase / hydrolase inhibitor / extra-cellular matrix / catalytic zinc / sA-sB loop / Alternative splicing / Cleavage on pair of basic residues / Glycoprotein / Membrane / Metal-binding / Metalloprotease / Notch signaling pathway / Phosphoprotein / Protease / SH3-binding / Transmembrane / Zymogen / Disease mutation / Extracellular matrix / Metalloenzyme inhibitor / Metalloprotease inhibitor / Secreted / Sensory transduction / Vision
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / germinal center formation / cellular response to high density lipoprotein particle stimulus / platelet dense granule lumen / negative regulation of membrane protein ectodomain proteolysis / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / metalloendopeptidase inhibitor activity ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / germinal center formation / cellular response to high density lipoprotein particle stimulus / platelet dense granule lumen / negative regulation of membrane protein ectodomain proteolysis / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / metalloendopeptidase inhibitor activity / Notch receptor processing / tumor necrosis factor binding / interleukin-6 receptor binding / positive regulation of T cell chemotaxis / TNF signaling / cytokine precursor processing / negative regulation of extracellular matrix disassembly / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / metallodipeptidase activity / spleen development / commissural neuron axon guidance / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / Notch binding / positive regulation of vascular endothelial cell proliferation / wound healing, spreading of epidermal cells / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / Notch signaling pathway / cell adhesion mediated by integrin / amyloid precursor protein catabolic process / Signaling by EGFR / positive regulation of epidermal growth factor receptor signaling pathway / cytokine binding / basement membrane / Collagen degradation / membrane protein ectodomain proteolysis / T cell differentiation in thymus / positive regulation of blood vessel endothelial cell migration / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / positive regulation of G1/S transition of mitotic cell cycle / B cell differentiation / positive regulation of chemokine production / response to cytokine / response to hormone / cell motility / Constitutive Signaling by NOTCH1 HD Domain Mutants / negative regulation of transforming growth factor beta receptor signaling pathway / Activated NOTCH1 Transmits Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / ubiquitin binding / PDZ domain binding / protein processing / metalloendopeptidase activity / integrin binding / epidermal growth factor receptor signaling pathway / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / metallopeptidase activity / actin cytoskeleton / positive regulation of tumor necrosis factor production / peptidase activity / Platelet degranulation / positive regulation of cell growth / response to lipopolysaccharide / cell adhesion / extracellular matrix / endopeptidase activity / response to hypoxia / defense response to Gram-positive bacterium / apical plasma membrane / response to xenobiotic stimulus / positive regulation of cell migration / membrane raft / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / cell surface / proteolysis / extracellular region / membrane / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Protease inhibitor I35 (TIMP) / Proteinase inhibitor I35b (TIMP), C-terminal / Tissue inhibitor of metalloproteinase, conserved site / Tissue inhibitor of metalloproteinase / Tissue inhibitors of metalloproteinases signature. / Tissue inhibitor of metalloproteinase family. / Metallo-peptidase family M12 / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain ...Protease inhibitor I35 (TIMP) / Proteinase inhibitor I35b (TIMP), C-terminal / Tissue inhibitor of metalloproteinase, conserved site / Tissue inhibitor of metalloproteinase / Tissue inhibitors of metalloproteinases signature. / Tissue inhibitor of metalloproteinase family. / Metallo-peptidase family M12 / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain / : / Metallo-peptidase family M12B Reprolysin-like / OB fold (Dihydrolipoamide Acetyltransferase, E2P) - #120 / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Netrin domain / NTR domain profile. / Tissue inhibitor of metalloproteinases-like, OB-fold / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / Beta Barrel / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Metalloproteinase inhibitor 3 / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.3 Å
AuthorsWisniewska, M. / Goettig, P. / Maskos, K. / Belouski, E. / Winters, D. / Hecht, R. / Black, R. / Bode, W.
CitationJournal: J.Mol.Biol. / Year: 2008
Title: Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex.
Authors: Wisniewska, M. / Goettig, P. / Maskos, K. / Belouski, E. / Winters, D. / Hecht, R. / Black, R. / Bode, W.
History
DepositionMar 15, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / 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 / _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_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ADAM 17
B: Metalloproteinase inhibitor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0164
Polymers42,9282
Non-polymers882
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2200 Å2
ΔGint-54 kcal/mol
Surface area17640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.447, 70.447, 156.728
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein ADAM 17 / A disintegrin and metalloproteinase domain 17 / TNF-alpha-converting enzyme / TNF-alpha convertase ...A disintegrin and metalloproteinase domain 17 / TNF-alpha-converting enzyme / TNF-alpha convertase / Snake venom-like protease / CD156b antigen


Mass: 28954.457 Da / Num. of mol.: 1 / Fragment: TACE catalytic domain (UNP RESIDUES 219-474) / Mutation: S266A, N452Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Cell line (production host): CHO / Organ (production host): ovary / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P78536, ADAM 17 endopeptidase
#2: Protein Metalloproteinase inhibitor 3 / TIMP-3 / Tissue inhibitor of metalloproteinases 3 / Protein MIG-5


Mass: 13973.272 Da / Num. of mol.: 1 / Fragment: N-TIMP-3 (UNP RESIDUES 24-144)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TIMP3 / Production host: Escherichia coli (E. coli) / References: UniProt: P35625
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 2

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Sample preparation

CrystalDensity Matthews: 2.26 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 309 K / pH: 4.5
Details: 100 mM sodium acetate/acetic acid, 25% polyethylene glycol 3,350, pH 4.5, VAPOR DIFFUSION, SITTING DROP, temperature 309K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelengthWavelength (Å)
SYNCHROTRONMPG/DESY, HAMBURG BW611.282
SYNCHROTRONMPG/DESY, HAMBURG BW621.280,1.2825,1.2790
Detector
TypeIDDetectorDateDetails (eV)
MAR CCD 165 mm1CCDDec 13, 2006MIRRORS
MAR CCD 165 mm2CCDDec 13, 2006MIRRORS
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SI 111 CHANNELSINGLE WAVELENGTHMx-ray1
2SI 111 CHANNELMADMx-ray2
Radiation wavelength
IDWavelength (Å)Relative weight
11.2821
21.281
31.28251
41.2791
ReflectionResolution: 2.3→20 Å / Num. obs: 16708 / % possible obs: 91 % / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 28.3 Å2 / Rsym value: 0.054 / Net I/σ(I): 31.6
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 4 % / Mean I/σ(I) obs: 8.2 / Rsym value: 0.167 / % possible all: 98.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MAD
Starting model: 1BKC

1bkc


Resolution: 2.3→19.59 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 1392278.82 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.284 922 5.1 %RANDOM
Rwork0.234 ---
obs0.234 18136 99.2 %-
all-16125 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.3794 Å2 / ksol: 0.286424 e/Å3
Displacement parametersBiso mean: 46.3 Å2
Baniso -1Baniso -2Baniso -3
1--0.6 Å20 Å20 Å2
2--1.93 Å20 Å2
3----1.33 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.39 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.32 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.3→19.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 2 190 3201
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.83
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it2.381.5
X-RAY DIFFRACTIONc_mcangle_it3.812
X-RAY DIFFRACTIONc_scbond_it3.352
X-RAY DIFFRACTIONc_scangle_it4.722.5
LS refinement shellResolution: 2.3→2.38 Å / Rfactor Rfree error: 0.037 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.371 100 5.9 %
Rwork0.302 1585 -
obs--94.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP

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