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- PDB-3b92: Novel thio-based TACE inhibitors Part 2: Rational design, synthes... -

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Basic information

Entry
Database: PDB / ID: 3b92
TitleNovel thio-based TACE inhibitors Part 2: Rational design, synthesis and SAR of thiol-contaning aryl sufones
ComponentsADAM 17
KeywordsHYDROLASE / TNF-alpha converting enzyme / aryl-sulfonamide / TACE inhibitors / Alternative splicing / Cleavage on pair of basic residues / Glycoprotein / Membrane / Metal-binding / Metalloprotease / Notch signaling pathway / Phosphorylation / Protease / SH3-binding / Transmembrane / Zinc / Zymogen
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding / tumor necrosis factor binding / positive regulation of T cell chemotaxis ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding / tumor necrosis factor binding / positive regulation of T cell chemotaxis / TNF signaling / germinal center formation / Regulated proteolysis of p75NTR / Release of Hh-Np from the secreting cell / commissural neuron axon guidance / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / wound healing, spreading of epidermal cells / Notch binding / negative regulation of cold-induced thermogenesis / positive regulation of leukocyte chemotaxis / CD163 mediating an anti-inflammatory response / positive regulation of vascular endothelial cell proliferation / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / Signaling by EGFR / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / Collagen degradation / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of blood vessel endothelial cell migration / positive regulation of G1/S transition of mitotic cell cycle / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / positive regulation of chemokine production / Notch signaling pathway / spleen development / Constitutive Signaling by NOTCH1 HD Domain Mutants / Activated NOTCH1 Transmits Signal to the Nucleus / B cell differentiation / cell motility / PDZ domain binding / negative regulation of transforming growth factor beta receptor signaling pathway / protein processing / metalloendopeptidase activity / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / SH3 domain binding / metallopeptidase activity / actin cytoskeleton / integrin binding / T cell differentiation in thymus / peptidase activity / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / cell adhesion / positive regulation of cell migration / defense response to Gram-positive bacterium / response to xenobiotic stimulus / membrane raft / apical plasma membrane / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / cell surface / proteolysis / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Metallo-peptidase family M12 / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain / Metallo-peptidase family M12B Reprolysin-like / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily ...Metallo-peptidase family M12 / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / ADAM10/ADAM17 catalytic domain / Metallo-peptidase family M12B Reprolysin-like / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-440 / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsWei, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones.
Authors: Bandarage, U.K. / Wang, T. / Come, J.H. / Perola, E. / Wei, Y. / Rao, B.G.
History
DepositionNov 2, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2007Provider: 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_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.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
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ADAM 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,6534
Polymers29,2381
Non-polymers4153
Water4,414245
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.720, 76.720, 105.930
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212

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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: 29237.734 Da / Num. of mol.: 1 / Fragment: TACE proteinase domain, UNP residues 216-474 / Mutation: S266A, N452Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Plasmid: pbev11topo / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P78536, ADAM 17 endopeptidase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-440 / 3-{[4-(but-2-yn-1-yloxy)phenyl]sulfonyl}propane-1-thiol


Mass: 284.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16O3S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 245 / 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: 2.67 Å3/Da / Density % sol: 53.86 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 30% PEGMME 550, 0.1M BIS-TRIS, 50mM CaCl2, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 16, 2003 / Details: mirrors
RadiationMonochromator: Ni mirrors and Ni filter / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. obs: 21191 / Biso Wilson estimate: 12.6 Å2

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Processing

Software
NameVersionClassification
CNX2005refinement
ADSCQuantumdata collection
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1bkc

1bkc


Resolution: 2→19.75 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 2780637.34 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2
RfactorNum. reflection% reflectionSelection details
Rfree0.28 1081 5.1 %RANDOM
Rwork0.238 ---
obs-21043 95.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 35.4185 Å2 / ksol: 0.332427 e/Å3
Displacement parametersBiso mean: 37.3 Å2
Baniso -1Baniso -2Baniso -3
1--1.84 Å20 Å20 Å2
2---1.84 Å20 Å2
3---3.69 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.36 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.61 Å0.51 Å
Refinement stepCycle: LAST / Resolution: 2→19.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2052 0 20 245 2317
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d0.63
X-RAY DIFFRACTIONc_mcbond_it1.431.5
X-RAY DIFFRACTIONc_mcangle_it2.412
X-RAY DIFFRACTIONc_scbond_it2.012
X-RAY DIFFRACTIONc_scangle_it3.062.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.03 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.406 181 5.8 %
Rwork0.409 2930 -
obs--86.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.pprotein.top
X-RAY DIFFRACTION2240.param240.top
X-RAY DIFFRACTION3water_rep.parwater_rep.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5parmxray.xpl

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