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- PDB-6yd2: X-ray structure of furin in complex with the canavanine-based inh... -

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Entry
Database: PDB / ID: 6yd2
TitleX-ray structure of furin in complex with the canavanine-based inhibitor 4-aminomethyl-phenylacetyl-canavanine-Tle-Arg-Amba
Components
  • 4-aminomethyl-phenylacetyl-canavanine-Tle-Arg-Amba
  • Furin
KeywordsHYDROLASE / Protease / Inhibitor / Complex / Canavanine
Function / homology
Function and homology information


furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / regulation of cholesterol transport / signal peptide processing / negative regulation of low-density lipoprotein particle receptor catabolic process ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / regulation of cholesterol transport / signal peptide processing / negative regulation of low-density lipoprotein particle receptor catabolic process / peptide biosynthetic process / Pre-NOTCH Processing in Golgi / nerve growth factor binding / Synthesis and processing of ENV and VPU / cytokine precursor processing / Formation of the cornified envelope / secretion by cell / Signaling by PDGF / trans-Golgi network transport vesicle / Signaling by NODAL / heparan sulfate binding / blastocyst formation / Elastic fibre formation / peptide hormone processing / positive regulation of membrane protein ectodomain proteolysis / zymogen activation / CD163 mediating an anti-inflammatory response / Activation of Matrix Metalloproteinases / Maturation of hRSV A proteins / regulation of protein catabolic process / TGF-beta receptor signaling activates SMADs / Collagen degradation / collagen catabolic process / Uptake and function of anthrax toxins / Respiratory syncytial virus (RSV) attachment and entry / extracellular matrix disassembly / regulation of signal transduction / endopeptidase activator activity / Removal of aminoterminal propeptides from gamma-carboxylated proteins / viral life cycle / extracellular matrix organization / serine-type peptidase activity / peptide binding / transforming growth factor beta receptor signaling pathway / protein maturation / negative regulation of inflammatory response to antigenic stimulus / serine-type endopeptidase inhibitor activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / trans-Golgi network / protein processing / Golgi lumen / peptidase activity / heparin binding / protease binding / endopeptidase activity / viral translation / amyloid fibril formation / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / Attachment and Entry / positive regulation of viral entry into host cell / endosome membrane / viral protein processing / membrane raft / Amyloid fiber formation / Golgi membrane / serine-type endopeptidase activity / cell surface / endoplasmic reticulum / extracellular exosome / extracellular region / metal ion binding / membrane / plasma membrane
Similarity search - Function
Peptidase S8, pro-domain / Peptidase S8, pro-domain superfamily / Peptidase S8 pro-domain / Kexin/furin catalytic domain / P domain / Proprotein convertase P-domain / P/Homo B domain profile. / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, aspartic acid active site. ...Peptidase S8, pro-domain / Peptidase S8, pro-domain superfamily / Peptidase S8 pro-domain / Kexin/furin catalytic domain / P domain / Proprotein convertase P-domain / P/Homo B domain profile. / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, aspartic acid active site. / Peptidase S8, subtilisin, Asp-active site / Serine proteases, subtilase family, serine active site. / Peptidase S8, subtilisin, Ser-active site / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
PHOSPHATE ION / Furin
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDahms, S.O.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM 2730 Austria
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: The Basicity Makes the Difference: Improved Canavanine-Derived Inhibitors of the Proprotein Convertase Furin.
Authors: Lam van, T.V. / Heindl, M.R. / Schlutt, C. / Bottcher-Friebertshauser, E. / Bartenschlager, R. / Klebe, G. / Brandstetter, H. / Dahms, S.O. / Steinmetzer, T.
History
DepositionMar 20, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 2.0Oct 19, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_2 / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_database_status / pdbx_entity_nonpoly / pdbx_entity_src_syn / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_ref / struct_ref_seq / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_alt_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.gene_src_common_name / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_special_symmetry.label_asym_id / _struct_conn.pdbx_leaving_atom_flag / _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_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_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_asym_id / _struct_site_gen.auth_comp_id / _struct_site_gen.auth_seq_id / _struct_site_gen.label_asym_id / _struct_site_gen.label_comp_id / _struct_site_gen.label_seq_id
Revision 3.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond / Item: _atom_site.auth_atom_id / _atom_site.label_atom_id
Revision 3.1Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Furin
611: 4-aminomethyl-phenylacetyl-canavanine-Tle-Arg-Amba
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,57812
Polymers53,0852
Non-polymers49310
Water7,981443
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)131.506, 131.506, 155.243
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6
Components on special symmetry positions
IDModelComponents
11A-606-

NA

21A-1085-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules A611

#1: Protein Furin / Dibasic-processing enzyme / Paired basic amino acid residue-cleaving enzyme / PACE


Mass: 52388.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FURIN, FUR, PACE, PCSK3 / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P09958, furin
#2: Protein/peptide 4-aminomethyl-phenylacetyl-canavanine-Tle-Arg-Amba


Mass: 696.863 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 6 types, 453 molecules

#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 443 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.7 Å3/Da / Density % sol: 66.74 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: CRYSTALLIZATION SOLUTION: 100MM MES, 200MM K/NAH2PO4, PH 5.5-6.0, 2 M NACL; RESERVOIR SOLUTION: 3-4M NACL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Sep 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.8→43.1 Å / Num. obs: 72501 / % possible obs: 98.4 % / Redundancy: 17.2 % / Biso Wilson estimate: 25.62 Å2 / Rrim(I) all: 0.137 / Net I/σ(I): 19.2
Reflection shellResolution: 1.8→1.91 Å / Num. unique obs: 11497 / Rrim(I) all: 2.039

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHENIX1.17.1refinement
Cootmodel building
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JXH

5jxh


Resolution: 1.8→43.05 Å / SU ML: 0.1739 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.1993
RfactorNum. reflection% reflection
Rfree0.1771 3566 4.93 %
Rwork0.1575 --
obs0.1584 72363 98.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 32.05 Å2
Refinement stepCycle: LAST / Resolution: 1.8→43.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3608 0 71 443 4122
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00963816
X-RAY DIFFRACTIONf_angle_d1.03275208
X-RAY DIFFRACTIONf_chiral_restr0.0606560
X-RAY DIFFRACTIONf_plane_restr0.0078693
X-RAY DIFFRACTIONf_dihedral_angle_d22.30552275
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.820.34071700.29252664X-RAY DIFFRACTION98.37
1.82-1.850.28741330.27552745X-RAY DIFFRACTION98.6
1.85-1.880.29771440.24672699X-RAY DIFFRACTION98.75
1.88-1.910.26231450.24152679X-RAY DIFFRACTION98.64
1.91-1.940.24191360.21662742X-RAY DIFFRACTION98.73
1.94-1.970.23611320.19842729X-RAY DIFFRACTION98.96
1.97-2.010.19941270.19262745X-RAY DIFFRACTION98.76
2.01-2.050.21821410.18022728X-RAY DIFFRACTION98.93
2.05-2.090.20661440.17082743X-RAY DIFFRACTION99.14
2.09-2.130.19371440.16072710X-RAY DIFFRACTION99.06
2.13-2.180.18671440.15012750X-RAY DIFFRACTION99.04
2.18-2.240.17191500.14662757X-RAY DIFFRACTION99.42
2.24-2.30.17251210.14792751X-RAY DIFFRACTION99.1
2.3-2.370.17371360.14522781X-RAY DIFFRACTION99.32
2.37-2.440.16211250.14982625X-RAY DIFFRACTION93.89
2.44-2.530.19891190.14512366X-RAY DIFFRACTION84.9
2.53-2.630.17941330.15232763X-RAY DIFFRACTION98.7
2.63-2.750.16741540.15422774X-RAY DIFFRACTION99.73
2.75-2.90.2051470.15892787X-RAY DIFFRACTION99.66
2.9-3.080.17531480.16582811X-RAY DIFFRACTION99.83
3.08-3.320.17261490.14682817X-RAY DIFFRACTION99.83
3.32-3.650.16931600.13542822X-RAY DIFFRACTION99.97
3.65-4.180.14081480.11842856X-RAY DIFFRACTION99.97
4.18-5.260.11621560.12092906X-RAY DIFFRACTION99.93
5.26-43.050.18721600.20023047X-RAY DIFFRACTION98.98
Refinement TLS params.Method: refined / Origin x: 35.194079995 Å / Origin y: -37.5554575822 Å / Origin z: 0.287096712063 Å
111213212223313233
T0.159788657838 Å2-0.00151052865061 Å20.00774280667158 Å2-0.213686565094 Å20.00110763977963 Å2--0.19495414277 Å2
L0.284437825645 °20.0437258905368 °20.0275201631415 °2-0.459235133963 °20.242312343337 °2--0.53419192537 °2
S-0.00624930603902 Å °0.0369049584777 Å °-0.0214704992672 Å °-0.0325198498499 Å °0.00237841394348 Å °0.0177039794787 Å °-0.00863164406077 Å °-0.0705420566636 Å °-3.01899368099E-6 Å °
Refinement TLS groupSelection details: chain A

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