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- PDB-3lea: Crystal structure of the catalytic domain of TACE with Isoindolin... -

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Basic information

Entry
Database: PDB / ID: 3lea
TitleCrystal structure of the catalytic domain of TACE with Isoindolinone-biphenyl-hydantoin inhibitor
ComponentsDisintegrin and metalloproteinase domain-containing protein 17
KeywordsHYDROLASE / GLYCOPROTEIN / MEMBRANE / METAL-BINDING / METALLOPROTEASE / NOTCH SIGNALING PATHWAY / PHOSPHOPROTEIN / PROTEASE / TRANSMEMBRANE / 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 / positive regulation of leukocyte chemotaxis / 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 / Notch binding / wound healing, spreading of epidermal cells / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of vascular endothelial cell proliferation / cell adhesion mediated by integrin / positive regulation of epidermal growth factor receptor signaling pathway / 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 G1/S transition of mitotic cell cycle / positive regulation of blood vessel endothelial cell migration / Nuclear signaling by ERBB4 / Growth hormone receptor signaling / 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 / PDZ domain binding / cell motility / negative regulation of transforming growth factor beta receptor signaling pathway / metalloendopeptidase activity / protein processing / 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
ISOPROPYL ALCOHOL / Chem-Z93 / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsOrth, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Biaryl substituted hydantoin compounds as TACE inhibitors.
Authors: Yu, W. / Tong, L. / Kim, S.H. / Wong, M.K. / Chen, L. / Yang, D.Y. / Shankar, B.B. / Lavey, B.J. / Zhou, G. / Kosinski, A. / Rizvi, R. / Li, D. / Feltz, R.J. / Piwinski, J.J. / Rosner, K.E. ...Authors: Yu, W. / Tong, L. / Kim, S.H. / Wong, M.K. / Chen, L. / Yang, D.Y. / Shankar, B.B. / Lavey, B.J. / Zhou, G. / Kosinski, A. / Rizvi, R. / Li, D. / Feltz, R.J. / Piwinski, J.J. / Rosner, K.E. / Shih, N.Y. / Siddiqui, M.A. / Guo, Z. / Orth, P. / Shah, H. / Sun, J. / Umland, S. / Lundell, D.J. / Niu, X. / Kozlowski, J.A.
History
DepositionJan 14, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / 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_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_label_asym_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_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.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_label_asym_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 1.3Sep 6, 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: Disintegrin and metalloproteinase domain-containing protein 17
B: Disintegrin and metalloproteinase domain-containing protein 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,1847
Polymers61,1382
Non-polymers1,0465
Water7,764431
1
A: Disintegrin and metalloproteinase domain-containing protein 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0623
Polymers30,5691
Non-polymers4932
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Disintegrin and metalloproteinase domain-containing protein 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,1224
Polymers30,5691
Non-polymers5533
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.481, 112.540, 51.272
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Disintegrin and metalloproteinase domain-containing protein 17 / ADAM 17 / TNF-alpha-converting enzyme / TNF-alpha convertase / Snake venom-like protease


Mass: 30569.135 Da / Num. of mol.: 2 / Fragment: residues 215-476 / Mutation: S266A, V353G, N452Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P78536, ADAM 17 endopeptidase
#2: Chemical ChemComp-Z93 / 2-{[(4R)-2,5-dioxo-4-(4-pyridin-3-ylphenyl)imidazolidin-4-yl]methyl}-6-methoxy-1-oxo-1H-isoindolium / N-[(1S)-2-AMINO-1-(2,4-DICHLOROBENZYL)ETHYL]-5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]THIOPHENE-2-CARBOXAMIDE


Mass: 427.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19N4O4
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 431 / 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: 2.42 Å3/Da / Density % sol: 49.13 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 15% PEG 6K, 10% 2-PROPANOL, 100 MM SODIUM ACETATE, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Aug 3, 2006
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 40918 / Num. obs: 40796 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 26.51 Å2
Reflection shellResolution: 2→2.07 Å / % possible all: 10

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
BUSTER2.9.3refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BKC

1bkc


Resolution: 2→46.63 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.219 1984 4.87 %RANDOM
Rwork0.1761 ---
obs-40749 --
Displacement parametersBiso mean: 27.09 Å2
Baniso -1Baniso -2Baniso -3
1-2.9709 Å20 Å20 Å2
2---0.2935 Å20 Å2
3----2.6774 Å2
Refine analyzeLuzzati coordinate error obs: 0.205 Å
Refinement stepCycle: LAST / Resolution: 2→46.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4037 0 70 431 4538
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.01
X-RAY DIFFRACTIONo_bond_d_na
X-RAY DIFFRACTIONo_bond_d_prot
X-RAY DIFFRACTIONo_angle_d
X-RAY DIFFRACTIONo_angle_d_na
X-RAY DIFFRACTIONo_angle_d_prot
X-RAY DIFFRACTIONo_angle_deg1.04
X-RAY DIFFRACTIONo_angle_deg_na
X-RAY DIFFRACTIONo_angle_deg_prot
X-RAY DIFFRACTIONo_dihedral_angle_d
X-RAY DIFFRACTIONo_dihedral_angle_d_na
X-RAY DIFFRACTIONo_dihedral_angle_d_prot
X-RAY DIFFRACTIONo_improper_angle_d
X-RAY DIFFRACTIONo_improper_angle_d_na
X-RAY DIFFRACTIONo_improper_angle_d_prot
X-RAY DIFFRACTIONo_mcbond_it
X-RAY DIFFRACTIONo_mcangle_it
X-RAY DIFFRACTIONo_scbond_it
X-RAY DIFFRACTIONo_scangle_it
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.235 137 4.63 %
Rwork0.201 2822 -
all0.203 2959 -
obs--99.63 %

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