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

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Basic information

Entry
Database: PDB / ID: 4omc
TitleX-ray structure of human furin in complex with the competitive inhibitor meta-guanidinomethyl-Phac-RVR-Amba
Components
  • Furin
  • meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
KeywordsHYDROLASE/HYDROLASE INHIBITOR / pro-protein convertase / serine protease / competitive inhibitor / protease-inhibitor complex / HYDROLASE-HYDROLASE INHIBITOR complex
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
meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine / FORMIC ACID / Furin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsDahms, S.O. / Than, M.E.
CitationJournal: Acs Chem.Biol. / Year: 2014
Title: X-ray Structures of Human Furin in Complex with Competitive Inhibitors.
Authors: Dahms, S.O. / Hardes, K. / Becker, G.L. / Steinmetzer, T. / Brandstetter, H. / Than, M.E.
History
DepositionJan 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 9, 2014Provider: repository / Type: Initial release
Revision 1.1May 28, 2014Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)320,71160
Polymers318,74712
Non-polymers1,96448
Water24,2481346
1
A: Furin
H: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-38 kcal/mol
Surface area17090 Å2
MethodPISA
2
B: Furin
I: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-38 kcal/mol
Surface area17000 Å2
MethodPISA
3
C: Furin
J: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2260 Å2
ΔGint-37 kcal/mol
Surface area17060 Å2
MethodPISA
4
D: Furin
K: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-37 kcal/mol
Surface area16980 Å2
MethodPISA
5
E: Furin
L: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-38 kcal/mol
Surface area16910 Å2
MethodPISA
6
F: Furin
N: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,45210
Polymers53,1252
Non-polymers3278
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-38 kcal/mol
Surface area17010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.178, 152.849, 168.306
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 (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P09958, furin
#2: Protein/peptide
meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine


Type: PolypeptidePeptide / Class: Enzyme inhibitor / Mass: 735.926 Da / Num. of mol.: 6 / Source method: obtained synthetically
References: meta-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)benzamidine

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Non-polymers , 4 types, 1394 molecules

#3: Chemical...
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 24 / 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 / Water


Mass: 18.015 Da / Num. of mol.: 1346 / 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: 2.85 Å3/Da / Density % sol: 56.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 50mM Tris, 2.8M sodium formate, 0.015mM 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: May 29, 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: 2.3→50 Å / Num. all: 161839 / Num. obs: 160915 / % possible obs: 99.4 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.8 % / Biso Wilson estimate: 31.4 Å2 / Rsym value: 0.012 / Net I/σ(I): 9.69
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 3.8 % / Mean I/σ(I) obs: 2.63 / Num. unique all: 25523 / Rsym value: 0.051 / % possible all: 98.5

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Processing

Software
NameClassification
MxCuBEdata collection
PHASERphasing
CNSrefinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50 Å / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2164 8055 -shells
Rwork0.1848 ---
all-161540 --
obs-160803 99.5 %-
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21650 0 96 1346 23092
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.0079
X-RAY DIFFRACTIONc_mcangle_it2.71
X-RAY DIFFRACTIONc_mcbond_it1.827
LS refinement shellResolution: 2.3→2.4 Å
RfactorNum. reflection
Rfree0.2927 1074
Rwork0.2514 -
obs-19835

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