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- PDB-3kmc: Crystal structure of catalytic domain of TACE with tartrate-based... -

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Basic information

Entry
Database: PDB / ID: 3kmc
TitleCrystal structure of catalytic domain of TACE with tartrate-based inhibitor
ComponentsTNF-alpha-converting enzyme
KeywordsHYDROLASE / A disintegrin and metalloproteinase domain 17 / TNF-alpha-converting enzyme / TNF-alpha convertase / Snake venom-like protease / Cleavage on pair of basic residues / Glycoprotein / Membrane / Metal-binding / Metalloprotease / Notch signaling pathway / Phosphoprotein / Protease / Zymogen
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / : / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / : / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / production of molecular mediator involved in inflammatory response / 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 / cytokine precursor processing / positive regulation of leukocyte chemotaxis / regulation of axon regeneration / metallodipeptidase activity / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / commissural neuron axon guidance / regulation of neuron migration / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / germinal center formation / Notch binding / wound healing, spreading of epidermal cells / positive regulation of vascular endothelial cell proliferation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / Signaling by EGFR / amyloid precursor protein catabolic process / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / 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 / spleen development / Notch signaling pathway / Constitutive Signaling by NOTCH1 HD Domain Mutants / Activated NOTCH1 Transmits Signal to the Nucleus / B cell differentiation / PDZ domain binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell motility / negative regulation of transforming growth factor beta receptor signaling pathway / metalloendopeptidase activity / protein processing / SH3 domain binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / integrin binding / epidermal growth factor receptor signaling pathway / metallopeptidase activity / positive regulation of tumor necrosis factor production / T cell differentiation in thymus / peptidase activity / actin cytoskeleton / negative regulation of neuron projection development / positive regulation of cell growth / response to lipopolysaccharide / endopeptidase activity / response to hypoxia / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / apical plasma membrane / membrane raft / response to xenobiotic stimulus / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / cell surface / proteolysis / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily ...ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / 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
3,N(D,L-[2-(HYDROXYAMINO-CARBONYL)METHYL]-4-METHYL PENTANOYL)L-3-(TERT-BUTYL)GLYCYL-L-ALANINE / Chem-403 / Chem-INN / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsOrth, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors.
Authors: Rosner, K.E. / Guo, Z. / Orth, P. / Shipps, G.W. / Belanger, D.B. / Chan, T.Y. / Curran, P.J. / Dai, C. / Deng, Y. / Girijavallabhan, V.M. / Hong, L. / Lavey, B.J. / Lee, J.F. / Li, D. / ...Authors: Rosner, K.E. / Guo, Z. / Orth, P. / Shipps, G.W. / Belanger, D.B. / Chan, T.Y. / Curran, P.J. / Dai, C. / Deng, Y. / Girijavallabhan, V.M. / Hong, L. / Lavey, B.J. / Lee, J.F. / Li, D. / Liu, Z. / Popovici-Muller, J. / Ting, P.C. / Vaccaro, H. / Wang, L. / Wang, T. / Yu, W. / Zhou, G. / Niu, X. / Sun, J. / Kozlowski, J.A. / Lundell, D.J. / Madison, V. / McKittrick, B. / Piwinski, J.J. / Shih, N.Y. / Arshad Siddiqui, M. / Strickland, C.O.
History
DepositionNov 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.2Feb 27, 2013Group: Other
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software
Revision 1.4Oct 13, 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_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 1.5Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Nov 27, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TNF-alpha-converting enzyme
B: TNF-alpha-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,1236
Polymers61,1382
Non-polymers9844
Water5,405300
1
A: TNF-alpha-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0503
Polymers30,5691
Non-polymers4812
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TNF-alpha-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0723
Polymers30,5691
Non-polymers5032
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.313, 76.103, 103.768
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 TNF-alpha-converting enzyme / ADAM 17 / Disintegrin and metalloproteinase domain-containing protein 17 / TNF-alpha convertase / ...ADAM 17 / Disintegrin and metalloproteinase domain-containing protein 17 / TNF-alpha convertase / Snake venom-like protease


Mass: 30569.135 Da / Num. of mol.: 2 / Fragment: residues 215-476 / Mutation: S266A, V353G, Q452N
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-INN / N-{(2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}-3-methyl-L-valyl-N-(2-aminoethyl)-L-alaninamide


Type: peptide-like, Peptide-like / Class: Enzyme inhibitor / Mass: 415.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H37N5O5
References: 3,N(D,L-[2-(HYDROXYAMINO-CARBONYL)METHYL]-4-METHYL PENTANOYL)L-3-(TERT-BUTYL)GLYCYL-L-ALANINE
#4: Chemical ChemComp-403 / (2R,3R)-4-[4-(2-chlorophenyl)piperazin-1-yl]-2,3-dihydroxy-4-oxo-N-(2-thiophen-2-ylethyl)butanamide


Mass: 437.940 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24ClN3O4S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 300 / 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: 1

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Sample preparation

CrystalDensity Matthews: 2.4 Å3/Da / Density % sol: 48.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 5.6
Details: 15% PEG 6000, 10% 2-Propanol, 100 mM sodium citrate, pH 5.6, VAPOR DIFFUSION, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 3, 2006
Details: Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the ...Details: Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→40 Å / Num. obs: 54154 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 28.74 Å2
Reflection shellResolution: 1.8→1.83 Å / % possible all: 5

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Processing

Software
NameVersionClassification
CrystalCleardata collection
BUSTER2.9.2refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1bkc

1bkc


Resolution: 1.8→37.16 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2588 1033 1.93 %RANDOM
Rwork0.2237 ---
all-53494 --
obs-53494 --
Displacement parametersBiso mean: 34.73 Å2
Baniso -1Baniso -2Baniso -3
1--3.9839 Å20 Å20 Å2
2---0.7432 Å20 Å2
3---4.7271 Å2
Refine analyzeLuzzati coordinate error obs: 0.321 Å
Refinement stepCycle: LAST / Resolution: 1.8→37.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3931 0 53 300 4284
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.009
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_deg1.06
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

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