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- PDB-7qxy: X-ray structure of furin in complex with the dichlorophenylpyridi... -

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Basic information

Entry
Database: PDB / ID: 7qxy
TitleX-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 3
ComponentsFurin
KeywordsHYDROLASE / proprotein convertase / inhibitor / SARS-CoV-2 / protease / complex / furin
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 / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / peptide biosynthetic process ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / Assembly of active LPL and LIPC lipase complexes / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / peptide biosynthetic process / 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 / Formation of the cornified envelope / nerve growth factor binding / Signaling by PDGF / trans-Golgi network transport vesicle / blastocyst formation / Elastic fibre formation / heparan sulfate binding / Signaling by NODAL / regulation of endopeptidase activity / peptide hormone processing / zymogen activation / positive regulation of membrane protein ectodomain proteolysis / CD163 mediating an anti-inflammatory response / regulation of protein catabolic process / Activation of Matrix Metalloproteinases / TGF-beta receptor signaling activates SMADs / Uptake and function of anthrax toxins / protein maturation / 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 / serine-type endopeptidase inhibitor activity / trans-Golgi network / protein processing / Golgi lumen / heparin binding / peptidase activity / viral translation / endopeptidase activity / Induction of Cell-Cell Fusion / protease binding / Potential therapeutics for SARS / amyloid fibril formation / 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, 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 / Serine proteases, subtilase domain profile. / Peptidase S8, subtilisin-related / 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
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.478 Å
AuthorsDahms, S.O. / Brandstetter, H. / Pautsch, A.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM 2730 Austria
CitationJournal: Acs Chem.Biol. / Year: 2022
Title: Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.
Authors: Dahms, S.O. / Schnapp, G. / Winter, M. / Buttner, F.H. / Schleputz, M. / Gnamm, C. / Pautsch, A. / Brandstetter, H.
History
DepositionJan 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: 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: Furin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,00410
Polymers52,1121
Non-polymers8919
Water11,908661
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area780 Å2
ΔGint-65 kcal/mol
Surface area17730 Å2
Unit cell
Length a, b, c (Å)131.672, 131.672, 155.354
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-605-

NA

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 52112.312 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

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Non-polymers , 5 types, 670 molecules

#2: Chemical ChemComp-CA / CALCIUM ION


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


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-I1G / 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-ium-1-yl]propanoate


Mass: 643.584 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H38Cl2N7O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 661 / 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

Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: CRYSTALLIZATION SOLUTION: 100mM MES, 200mM K/NAH2PO4, PH 5.5, 2 M NACL; RESERVOIR SOLUTION: 3.0-3.2M NACL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999917 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Oct 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999917 Å / Relative weight: 1
ReflectionResolution: 1.478→114.031 Å / Num. obs: 87795 / % possible obs: 66.5 % / Redundancy: 39.2 % / Biso Wilson estimate: 18.89 Å2 / Rmerge(I) obs: 0.207 / Rsym value: 0.207 / Net I/σ(I): 16.4
Reflection shellResolution: 1.478→1.654 Å / Redundancy: 29.4 % / Rmerge(I) obs: 2.845 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 4388 / Rsym value: 2.845 / % possible all: 11.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (18-SEP-2020)refinement
PDB_EXTRACT3.27data extraction
XDSVERSION Jan 31, 2020data reduction
Aimless0.7.4data scaling
BUSTER2.11.7 (18-SEP-2020)phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jxg

5jxg


Resolution: 1.478→114.03 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.955 / SU R Cruickshank DPI: 0.08 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.079 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.069
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.1823 4274 4.87 %RANDOM
Rwork0.1705 ---
obs0.1711 87795 66.5 %-
Displacement parametersBiso max: 258.31 Å2 / Biso mean: 24.97 Å2 / Biso min: 7.33 Å2
Baniso -1Baniso -2Baniso -3
1-0.3415 Å20 Å20 Å2
2--0.3415 Å20 Å2
3----0.683 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.478→114.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3608 0 52 661 4321
Biso mean--19.07 44.96 -
Num. residues----473
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2199SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1263HARMONIC5
X-RAY DIFFRACTIONt_it3815HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion493SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6571SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7344HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg13217HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion4.1
X-RAY DIFFRACTIONt_other_torsion14.54
LS refinement shellResolution: 1.48→1.59 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2515 90 5.13 %
Rwork0.2093 1666 -
all0.2113 1756 -
obs--6.91 %
Refinement TLS params.Method: refined / Origin x: 34.9592 Å / Origin y: -37.687 Å / Origin z: 0.4363 Å
111213212223313233
T-0.0327 Å2-0.0001 Å20.0036 Å2-0.0016 Å20 Å2---0.0211 Å2
L0.1375 °2-0.0417 °2-0.0657 °2-0.2493 °20.1258 °2--0.5768 °2
S0.0073 Å °0.0123 Å °-0.002 Å °-0.0208 Å °-0.0146 Å °0.0102 Å °-0.0053 Å °-0.0641 Å °0.0073 Å °
Refinement TLS groupSelection details: { A|* }

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