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- PDB-3l0t: Crystal structure of catalytic domain of TACE with hydantoin inhibitor -

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Basic information

Entry
Database: PDB / ID: 3l0t
TitleCrystal structure of catalytic domain of TACE with hydantoin inhibitor
ComponentsDisintegrin and metalloproteinase domain-containing protein 17
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Metal-binding / Metalloprotease / Notch signaling pathway / Protease / HYDROLASE-HYDROLASE INHIBITOR complex
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 / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / interleukin-6 receptor binding / Notch receptor processing / tumor necrosis factor 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 / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / interleukin-6 receptor binding / Notch receptor processing / tumor necrosis factor binding / positive regulation of T cell chemotaxis / TNF signaling / germinal center formation / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / 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 / 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 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 / spleen development / Notch signaling pathway / 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 / positive regulation of tumor necrosis factor production / integrin binding / actin cytoskeleton / peptidase activity / T cell differentiation in thymus / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / 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
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-INN / ISOPROPYL ALCOHOL / Chem-Z94 / Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsOrth, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery and SAR of hydantoin TACE inhibitors.
Authors: Yu, W. / Guo, Z. / Orth, P. / Madison, V. / Chen, L. / Dai, C. / Feltz, R.J. / Girijavallabhan, V.M. / Kim, S.H. / Kozlowski, J.A. / Lavey, B.J. / Li, D. / Lundell, D. / Niu, X. / Piwinski, ...Authors: Yu, W. / Guo, Z. / Orth, P. / Madison, V. / Chen, L. / Dai, C. / Feltz, R.J. / Girijavallabhan, V.M. / Kim, S.H. / Kozlowski, J.A. / Lavey, B.J. / Li, D. / Lundell, D. / Niu, X. / Piwinski, J.J. / Popovici-Muller, J. / Rizvi, R. / Rosner, K.E. / Shankar, B.B. / Shih, N.Y. / Siddiqui, M.A. / Sun, J. / Tong, L. / Umland, S. / Wong, M.K. / Yang, D.Y. / Zhou, G.
History
DepositionDec 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Oct 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
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_alt_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_alt_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.pdbx_ptnr2_label_alt_id / _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_ref_seq_dif.details
Revision 1.4Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 6, 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: Disintegrin and metalloproteinase domain-containing protein 17
B: Disintegrin and metalloproteinase domain-containing protein 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0388
Polymers61,1382
Non-polymers9006
Water4,594255
1
A: Disintegrin and metalloproteinase domain-containing protein 17
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,1104
Polymers30,5691
Non-polymers5413
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)30,9284
Polymers30,5691
Non-polymers3593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.198, 75.512, 102.724
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 261 molecules

#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-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#5: Chemical ChemComp-Z94 / N-{4-[(4S)-2,5-dioxoimidazolidin-4-yl]phenyl}acetamide / 2-(5-CARBAMIMIDOYL-2-HYDROXY-BENZYLAMINO)-PROPIONIC ACID


Mass: 233.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11N3O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.35 Å3/Da / Density % sol: 47.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 15% PEG 6k, 10% 2-Propanol, 100 mM sodium citrate, pH 5.6, VAPOR DIFFUSION, HANGING DROP, 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: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.92→50 Å / Num. all: 44802 / Num. obs: 44264 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 28.8 Å2
Reflection shellResolution: 1.92→1.99 Å / % possible all: 10

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Processing

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

1bkc


Resolution: 1.92→28.11 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2388 835 1.89 %RANDOM
Rwork0.2122 ---
obs-44155 --
Displacement parametersBiso mean: 32.38 Å2
Baniso -1Baniso -2Baniso -3
1--5.0194 Å20 Å20 Å2
2--4.6779 Å20 Å2
3---0.3415 Å2
Refine analyzeLuzzati coordinate error obs: 0.262 Å
Refinement stepCycle: LAST / Resolution: 1.92→28.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3903 0 56 255 4214
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_deg1.08
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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