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- PDB-4ryd: X-ray structure of human furin in complex with the competitive in... -

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Basic information

Entry
Database: PDB / ID: 4ryd
TitleX-ray structure of human furin in complex with the competitive inhibitor para-guanidinomethyl-Phac-R-Tle-R-Amba
Components
  • Furin
  • para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
KeywordsHydrolase/Hydrolase Inhibitor / competitive inhibitor / pro-protein convertase / serine protease / Hydrolase-Hydrolase Inhibitor complex
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 / nerve growth factor binding / Pre-NOTCH Processing in Golgi / 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 / Uptake and function of anthrax toxins / collagen catabolic process / 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 / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / negative regulation of inflammatory response to antigenic stimulus / trans-Golgi network / serine-type endopeptidase inhibitor activity / protein processing / Golgi lumen / peptidase activity / heparin binding / protease binding / endopeptidase activity / amyloid fibril formation / viral translation / 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 / Amyloid fiber formation / membrane raft / 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 / Peptidase S8/S53 domain / Peptidase S8/S53 domain / Subtilase family / Galactose-binding domain-like / Furin-like repeat / Furin-like repeats / 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
para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine / FORMIC ACID / Furin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsDahms, S.O. / Than, M.E.
CitationJournal: Chemmedchem / Year: 2015
Title: Novel Furin Inhibitors with Potent Anti-infectious Activity.
Authors: Hardes, K. / Becker, G.L. / Lu, Y. / Dahms, S.O. / Kohler, S. / Beyer, W. / Sandvig, K. / Yamamoto, H. / Lindberg, I. / Walz, L. / von Messling, V. / Than, M.E. / Garten, W. / Steinmetzer, T.
History
DepositionDec 15, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Structure summary
Revision 1.2Jul 15, 2015Group: Database references
Revision 1.3Jul 10, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / 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 / _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_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_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_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_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Furin
B: Furin
C: Furin
D: Furin
E: Furin
F: Furin
H: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
I: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
J: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
K: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
L: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
N: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)320,51954
Polymers318,83112
Non-polymers1,68842
Water36,6432034
1
A: Furin
H: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2090 Å2
ΔGint-37 kcal/mol
Surface area17030 Å2
MethodPISA
2
B: Furin
I: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1810 Å2
ΔGint-38 kcal/mol
Surface area16880 Å2
MethodPISA
3
C: Furin
J: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2100 Å2
ΔGint-37 kcal/mol
Surface area17020 Å2
MethodPISA
4
D: Furin
K: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint-37 kcal/mol
Surface area16880 Å2
MethodPISA
5
E: Furin
L: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2100 Å2
ΔGint-37 kcal/mol
Surface area16820 Å2
MethodPISA
6
F: Furin
N: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4209
Polymers53,1392
Non-polymers2817
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1820 Å2
ΔGint-37 kcal/mol
Surface area16800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.652, 152.701, 168.398
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 / Protein/peptide , 2 types, 12 molecules ABCDEFHIJKLN

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


Mass: 52388.602 Da / Num. of mol.: 6 / Fragment: UNP residues 108-574
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FUR, FURIN, PACE, PCSK3 / Plasmid: pHLsec / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P09958, furin
#2: Protein/peptide
para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine


Type: Polypeptide / Class: Enzyme inhibitor / Mass: 749.953 Da / Num. of mol.: 6 / Source method: obtained synthetically
References: para-guanidinomethyl-phenylacetyl-Arg-(3-methylvaline)-Arg-(amidomethyl)benzamidine

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Non-polymers , 4 types, 2076 molecules

#3: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2034 / 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: 2.86 Å3/Da / Density % sol: 56.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 50mM Tris, 2.8M sodium formate, 15mM Cymal-7, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 31, 2013 / Details: mirrors
RadiationMonochromator: double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 194799 / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.4 % / Biso Wilson estimate: 29.9 Å2 / Rsym value: 0.135
Reflection shellResolution: 2.15→2.28 Å / Mean I/σ(I) obs: 1.95 / Num. unique all: 30975 / Rsym value: 0.693 / % possible all: 97.7

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Processing

Software
NameClassification
MxCuBEdata collection
PHASERphasing
CNSrefinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→50 Å / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.2186 9740 shells
Rwork0.1862 --
all-197882 -
obs-194614 -
Refinement stepCycle: LAST / Resolution: 2.15→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21656 0 78 2034 23768
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.0076
X-RAY DIFFRACTIONc_angle_deg1.39413
LS refinement shellResolution: 2.15→2.25 Å / Rfactor Rfree: 0.307 / Rfactor Rwork: 0.268

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