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- PDB-1zxc: Crystal structure of catalytic domain of TNF-alpha converting enz... -

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Basic information

Entry
Database: PDB / ID: 1zxc
TitleCrystal structure of catalytic domain of TNF-alpha converting enzyme (TACE) with inhibitor
ComponentsADAM 17
KeywordsHYDROLASE / TACE/ADAM-17 / TACE-Inhibitor complex / Zn-endopeptidase
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-IH6 / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsLevin, J.I. / Chen, J.M. / Laakso, L.M. / Du, M. / Schmid, J. / Xu, W. / Cummons, T. / Xu, J. / Zhang, Y. / Jin, G. ...Levin, J.I. / Chen, J.M. / Laakso, L.M. / Du, M. / Schmid, J. / Xu, W. / Cummons, T. / Xu, J. / Zhang, Y. / Jin, G. / Cowling, R. / Barone, D. / Skotnicki, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates.
Authors: Levin, J.I. / Chen, J.M. / Laakso, L.M. / Du, M. / Du, X. / Venkatesan, A.M. / Sandanayaka, V. / Zask, A. / Xu, J. / Xu, W. / Zhang, Y. / Skotnicki, J.S.
History
DepositionJun 7, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 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.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_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 1.4Aug 23, 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

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Assembly

Deposited unit
A: ADAM 17
B: ADAM 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,4026
Polymers59,4752
Non-polymers9284
Water3,117173
1
A: ADAM 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2013
Polymers29,7371
Non-polymers4642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: ADAM 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2013
Polymers29,7371
Non-polymers4642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.120, 59.170, 195.810
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 29737.342 Da / Num. of mol.: 2 / Mutation: yes
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Production host: Escherichia coli (E. coli) / 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-IH6 / (3S)-4-{[4-(BUT-2-YNYLOXY)PHENYL]SULFONYL}-N-HYDROXY-2,2-DIMETHYLTHIOMORPHOLINE-3-CARBOXAMIDE


Mass: 398.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H22N2O5S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 173 / 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: 2.2 Å3/Da / Density % sol: 42.5 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 5.4
Details: PEG 4000, isopropanol, NaCitrate, pH 5.4, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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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 4 / Detector: CCD / Date: May 1, 2000
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→20 Å / Num. all: 29248 / Num. obs: 25216 / % possible obs: 86.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.2→20 Å / % possible all: 86.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1bkc

1bkc


Resolution: 2.28→20 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.875 / SU B: 4.813 / SU ML: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.572 / ESU R Free: 0.32 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28506 1777 7.8 %RANDOM
Rwork0.20993 ---
all0.21584 26333 --
obs0.21584 22637 85.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.022 Å2
Baniso -1Baniso -2Baniso -3
1-1.44 Å20 Å20 Å2
2---1.05 Å20 Å2
3----0.39 Å2
Refinement stepCycle: LAST / Resolution: 2.28→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4100 0 54 173 4327
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224257
X-RAY DIFFRACTIONr_angle_refined_deg1.3921.9655756
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9915515
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.83625.096208
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.31715730
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1961516
X-RAY DIFFRACTIONr_chiral_restr0.1150.2593
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023264
X-RAY DIFFRACTIONr_nbd_refined0.2160.22150
X-RAY DIFFRACTIONr_nbtor_refined0.3060.22917
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1750.2286
X-RAY DIFFRACTIONr_metal_ion_refined0.2470.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2610.254
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1950.221
X-RAY DIFFRACTIONr_mcbond_it0.7071.52641
X-RAY DIFFRACTIONr_mcangle_it1.20424123
X-RAY DIFFRACTIONr_scbond_it1.70331852
X-RAY DIFFRACTIONr_scangle_it2.6554.51633
LS refinement shellResolution: 2.28→2.338 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 135 -
Rwork0.21 1484 -
obs-1484 86.72 %

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