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- PDB-6hzc: X-ray structure of furin in complex with the cyclic inhibitor c[g... -

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Basic information

Entry
Database: PDB / ID: 6hzc
TitleX-ray structure of furin in complex with the cyclic inhibitor c[glutaryl-BVK-Lys-Arg-Arg-Tle-Lys]-4-Amba
Components
  • Furin
  • LYS-ARG-ARG-TBG-LYS-00S
KeywordsHYDROLASE / protease / proprotein convertase / inhibitor / complex cyclic peptide
Function / homology
Function and homology information


furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / Assembly of active LPL and LIPC lipase complexes / peptide biosynthetic process / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / Assembly of active LPL and LIPC lipase complexes / peptide biosynthetic process / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / negative regulation of low-density lipoprotein particle receptor catabolic process / cytokine precursor processing / Pre-NOTCH Processing in Golgi / secretion by cell / Synthesis and processing of ENV and VPU / nerve growth factor binding / Formation of the cornified envelope / Signaling by PDGF / trans-Golgi network transport vesicle / blastocyst formation / Elastic fibre formation / heparan sulfate binding / Signaling by NODAL / positive regulation of membrane protein ectodomain proteolysis / zymogen activation / regulation of endopeptidase activity / peptide hormone processing / CD163 mediating an anti-inflammatory response / regulation of protein catabolic process / Activation of Matrix Metalloproteinases / TGF-beta receptor signaling activates SMADs / protein maturation / Uptake and function of anthrax toxins / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / regulation of signal transduction / Removal of aminoterminal propeptides from gamma-carboxylated proteins / negative regulation of inflammatory response to antigenic stimulus / viral life cycle / serine-type peptidase activity / extracellular matrix organization / transforming growth factor beta receptor signaling pathway / peptide binding / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / trans-Golgi network / serine-type endopeptidase inhibitor activity / protein processing / Golgi lumen / heparin binding / peptidase activity / viral translation / endopeptidase activity / Induction of Cell-Cell Fusion / protease binding / amyloid fibril formation / Potential therapeutics for SARS / Attachment and Entry / positive regulation of viral entry into host cell / viral protein processing / endosome membrane / membrane raft / Amyloid fiber formation / Golgi membrane / serine-type endopeptidase activity / cell surface / endoplasmic reticulum / extracellular exosome / extracellular region / membrane / metal ion binding / 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/S53 domain / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine 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/S53 domain / 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 / Serine proteases, subtilase domain profile. / Peptidase S8, subtilisin-related / Galactose-binding domain-like / Furin-like repeat / Furin-like repeats / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Growth factor receptor cysteine-rich domain superfamily / Galactose-binding-like domain superfamily / Jelly Rolls / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
2-[4-(aminomethyl)phenyl]ethanoic acid / PHOSPHATE ION / PENTANEDIAL / Furin
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDahms, S.O.
CitationJournal: Chemmedchem / Year: 2019
Title: Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin.
Authors: Van Lam van, T. / Ivanova, T. / Hardes, K. / Heindl, M.R. / Morty, R.E. / Bottcher-Friebertshauser, E. / Lindberg, I. / Than, M.E. / Dahms, S.O. / Steinmetzer, T.
History
DepositionOct 23, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 6, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Apr 3, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jan 24, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conn / struct_conn_type
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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _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_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _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_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_conn.ptnr2_symmetry / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Furin
B: LYS-ARG-ARG-TBG-LYS-00S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,98214
Polymers53,2242
Non-polymers75812
Water7,404411
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2590 Å2
ΔGint-67 kcal/mol
Surface area17700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.689, 131.689, 155.339
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-606-

NA

21A-1055-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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 LYS-ARG-ARG-TBG-LYS-00S


Mass: 835.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 8 types, 423 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 / Chloride


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


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


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-PTD / PENTANEDIAL / Glutaraldehyde


Mass: 100.116 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H8O2
#9: Chemical ChemComp-BVK / 2-[4-(aminomethyl)phenyl]ethanoic acid


Mass: 165.189 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H11NO2
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 411 / 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: 3.65 Å3/Da / Density % sol: 66.33 %
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, 3% DMSO; 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: 1.9→45.97 Å / Num. obs: 59568 / % possible obs: 94.4 % / Redundancy: 17.8 % / CC1/2: 0.999 / Rrim(I) all: 0.135 / Net I/σ(I): 20.23
Reflection shellResolution: 1.9→2.01 Å / Redundancy: 17.7 % / Mean I/σ(I) obs: 2.58 / Num. unique obs: 9595 / CC1/2: 0.804 / Rrim(I) all: 1.348 / % possible all: 95.8

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6EQV

6eqv


Resolution: 1.9→45.965 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.51
RfactorNum. reflection% reflection
Rfree0.1833 2923 4.92 %
Rwork0.1642 --
obs0.1651 59454 94.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→45.965 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3667 0 39 411 4117
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073835
X-RAY DIFFRACTIONf_angle_d0.8675234
X-RAY DIFFRACTIONf_dihedral_angle_d22.1352304
X-RAY DIFFRACTIONf_chiral_restr0.056562
X-RAY DIFFRACTIONf_plane_restr0.006696
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.93120.30261430.2512695X-RAY DIFFRACTION97
1.9312-1.96450.26481400.22462699X-RAY DIFFRACTION96
1.9645-2.00020.23951210.21362737X-RAY DIFFRACTION96
2.0002-2.03860.20431370.22691X-RAY DIFFRACTION96
2.0386-2.08030.21361380.19072673X-RAY DIFFRACTION96
2.0803-2.12550.23391510.18192672X-RAY DIFFRACTION95
2.1255-2.17490.20581350.17442642X-RAY DIFFRACTION95
2.1749-2.22930.21351430.16442632X-RAY DIFFRACTION94
2.2293-2.28960.19241220.16372601X-RAY DIFFRACTION92
2.2896-2.3570.19481170.1632550X-RAY DIFFRACTION90
2.357-2.4330.19231220.16462323X-RAY DIFFRACTION82
2.433-2.520.1888930.15942083X-RAY DIFFRACTION73
2.52-2.62090.18911340.17382603X-RAY DIFFRACTION92
2.6209-2.74010.19261430.17362796X-RAY DIFFRACTION98
2.7401-2.88460.23151510.17792793X-RAY DIFFRACTION98
2.8846-3.06530.16611510.17742824X-RAY DIFFRACTION99
3.0653-3.30190.19471540.15972813X-RAY DIFFRACTION99
3.3019-3.63410.15391590.14472849X-RAY DIFFRACTION99
3.6341-4.15960.14951470.12852872X-RAY DIFFRACTION99
4.1596-5.23950.14041580.13392916X-RAY DIFFRACTION99
5.2395-45.97860.18921640.18753067X-RAY DIFFRACTION98

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