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- PDB-5tzq: Crystal Structure of FPV039:Bmf BH3 complex -

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Basic information

Entry
Database: PDB / ID: 5tzq
TitleCrystal Structure of FPV039:Bmf BH3 complex
Components
  • Bcl-2-like protein FPV039
  • Bcl-2-modifying factor
KeywordsAPOPTOSIS / Bcl-2 / fowlpox virus / poxvirus / Bmf
Function / homology
Function and homology information


host cell mitochondrion / regulation of apoptotic process / apoptotic process
Similarity search - Function
Bcl-2-modifying factor / Bcl-2-modifying factor, apoptosis / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Bcl-2, Bcl-2 homology region 1-3 / Bcl2-like / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Bcl-2-modifying factor / Apoptosis regulator Bcl-2 homolog
Similarity search - Component
Biological speciesFowlpox virus
Gallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsAnasir, M.I. / Kvansakul, M.
Funding support Australia, 1items
OrganizationGrant numberCountry
Australian Research Council (ARC)FT130101349 Australia
CitationJournal: J Biol Chem / Year: 2017
Title: Structural basis of apoptosis inhibition by the fowlpox virus protein FPV039.
Authors: Mohd Ishtiaq Anasir / Sofia Caria / Michael A Skinner / Marc Kvansakul /
Abstract: Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by proapoptotic and prosurvival members of the B- ...Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by proapoptotic and prosurvival members of the B-cell lymphoma 2 (Bcl-2) protein family. To counter premature death of a virus-infected cell, poxviruses use a range of different molecular strategies including the mimicry of prosurvival Bcl-2 proteins. One such viral prosurvival protein is the fowlpox virus protein FPV039, which is a potent apoptosis inhibitor, but the precise molecular mechanism by which FPV039 inhibits apoptosis is unknown. To understand how fowlpox virus inhibits apoptosis, we examined FPV039 using isothermal titration calorimetry, small-angle X-ray scattering, and X-ray crystallography. Here, we report that the fowlpox virus prosurvival protein FPV039 promiscuously binds to cellular proapoptotic Bcl-2 and engages all major proapoptotic Bcl-2 proteins. Unlike other identified viral Bcl-2 proteins to date, FPV039 engaged with cellular proapoptotic Bcl-2 with affinities comparable with those of Bcl-2's endogenous cellular counterparts. Structural studies revealed that FPV039 adopts the conserved Bcl-2 fold observed in cellular prosurvival Bcl-2 proteins and closely mimics the structure of the prosurvival Bcl-2 family protein Mcl-1. Our findings suggest that FPV039 is a pan-Bcl-2 protein inhibitor that can engage all host BH3-only proteins, as well as Bcl-2-associated X, apoptosis regulator (Bax) and Bcl-2 antagonist/killer (Bak) proteins to inhibit premature apoptosis of an infected host cell. This work therefore provides a mechanistic platform to better understand FPV039-mediated apoptosis inhibition.
History
DepositionNov 22, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bcl-2-like protein FPV039
B: Bcl-2-like protein FPV039
C: Bcl-2-modifying factor
D: Bcl-2-modifying factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,21110
Polymers40,8394
Non-polymers3726
Water4,017223
1
A: Bcl-2-like protein FPV039
D: Bcl-2-modifying factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6686
Polymers20,4192
Non-polymers2484
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-11 kcal/mol
Surface area8270 Å2
MethodPISA
2
B: Bcl-2-like protein FPV039
C: Bcl-2-modifying factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5434
Polymers20,4192
Non-polymers1242
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-9 kcal/mol
Surface area8400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.602, 41.197, 67.825
Angle α, β, γ (deg.)90.00, 93.14, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Bcl-2-like protein FPV039


Mass: 17251.646 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Fowlpox virus (strain NVSL) / Strain: NVSL / Gene: FPV039
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
Strain (production host): DE3 / References: UniProt: Q9J5G4
#2: Protein/peptide Bcl-2-modifying factor


Mass: 3167.668 Da / Num. of mol.: 2 / Fragment: UNP residues 135-160 / Source method: obtained synthetically / Source: (synth.) Gallus gallus (chicken) / References: UniProt: A9XRG9
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 223 / 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: 2.11 Å3/Da / Density % sol: 41.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.2 / Details: 0.2M Sodium formate pH7.2, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.65→46.91 Å / Num. obs: 40942 / % possible obs: 99.9 % / Redundancy: 3.9 % / Biso Wilson estimate: 25.3 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.05 / Net I/σ(I): 10.7
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 3.9 % / Rmerge(I) obs: 1.09 / Mean I/σ(I) obs: 1.1 / Num. unique all: 1971 / CC1/2: 0.684 / % possible all: 98.6

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HW4

4hw4


Resolution: 1.65→44.417 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.57
RfactorNum. reflection% reflection
Rfree0.2046 2054 5.02 %
Rwork0.1742 --
obs0.1757 40943 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.65→44.417 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2566 0 24 223 2813
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082677
X-RAY DIFFRACTIONf_angle_d0.7823612
X-RAY DIFFRACTIONf_dihedral_angle_d15.4571605
X-RAY DIFFRACTIONf_chiral_restr0.05401
X-RAY DIFFRACTIONf_plane_restr0.005443
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.68840.36631200.38582555X-RAY DIFFRACTION98
1.6884-1.73060.37651540.36212539X-RAY DIFFRACTION98
1.7306-1.77740.36421230.33322558X-RAY DIFFRACTION99
1.7774-1.82970.34621480.30382572X-RAY DIFFRACTION99
1.8297-1.88880.27041360.25732589X-RAY DIFFRACTION99
1.8888-1.95630.23831530.22862543X-RAY DIFFRACTION99
1.9563-2.03460.22221430.18412598X-RAY DIFFRACTION99
2.0346-2.12720.2231350.17622584X-RAY DIFFRACTION99
2.1272-2.23940.19391540.15832587X-RAY DIFFRACTION100
2.2394-2.37970.19031580.14862556X-RAY DIFFRACTION99
2.3797-2.56340.18291180.15152667X-RAY DIFFRACTION100
2.5634-2.82130.1941270.14742642X-RAY DIFFRACTION100
2.8213-3.22940.21881590.16352591X-RAY DIFFRACTION100
3.2294-4.06830.14061040.15322670X-RAY DIFFRACTION99
4.0683-44.43330.18751220.15612638X-RAY DIFFRACTION96
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.5029-1.46961.3662.33990.64924.66290.01-0.0916-0.1757-0.03970.1208-0.13370.20270.0616-0.12750.2087-0.0140.01280.167-0.00750.263526.0699-2.564416.5477
23.4821-0.7991.95660.5156-0.27575.0414-0.0962-0.0872-0.0738-0.05680.05850.0247-0.0687-0.2501-0.00830.2156-0.03670.0210.1755-0.00570.225113.20964.68711.5504
35.5679-3.04592.89131.6877-1.48123.8358-0.07930.878-0.1879-1.13930.17721.09530.33590.1411-0.04430.3817-0.0439-0.04850.4414-0.04910.443822.9082-4.40013.5089
42.5181-0.36611.63632.50190.71363.8268-0.2046-0.330.19010.0770.2239-0.0801-0.40090.30260.00970.2299-0.0157-0.01050.2216-0.03760.249623.25328.79520.7363
51.7808-0.2609-0.43011.2068-0.04750.99590.0667-0.01130.0379-0.05510.0171-0.0050.15150.26230.01910.22780.0360.02320.23830.02540.251236.8558-6.83818.962
63.7465-1.3847-1.03721.3943-0.13853.9558-0.1193-0.98560.04440.14060.0969-0.18130.19530.7328-0.02930.30740.0774-0.03110.5104-0.0210.240548.2944-8.727826.8321
73.83340.0169-0.81843.72190.86313.943-0.0487-0.02790.4937-0.10760.13390.1244-0.40690.4483-0.12880.25640.029-0.04180.2718-0.02750.276651.2099-0.640711.9817
83.7745-0.2906-0.38250.8961-0.96641.2206-0.0165-0.60470.49920.1553-0.07040.1888-0.31930.073-0.02070.2710.0547-0.00910.3676-0.07410.303248.5073-2.935322.7921
92.7434-0.17021.14170.2999-0.20752.57170.0576-0.0202-0.172-0.115-0.0393-0.06050.38-0.0548-0.07190.28820.03640.00990.2084-0.01110.285442.358-11.867913.2617
104.10581.8341-0.69523.389-1.43314.5071-0.1077-0.3480.214-0.0499-0.08220.0074-0.13610.40390.03930.23590.0443-0.01980.3342-0.0030.307859.0317-6.802114.854
114.1203-0.66280.18664.8763-1.31588.6566-0.288-0.31640.19880.52440.13120.0768-0.9678-0.8780.160.27210.0557-0.02480.2907-0.050.26217.30112.562413.1793
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 6 through 37 )
2X-RAY DIFFRACTION2chain 'A' and (resid 38 through 98 )
3X-RAY DIFFRACTION3chain 'A' and (resid 99 through 111 )
4X-RAY DIFFRACTION4chain 'A' and (resid 112 through 142 )
5X-RAY DIFFRACTION5chain 'B' and (resid 5 through 27 )
6X-RAY DIFFRACTION6chain 'B' and (resid 28 through 65 )
7X-RAY DIFFRACTION7chain 'B' and (resid 66 through 82 )
8X-RAY DIFFRACTION8chain 'B' and (resid 83 through 109 )
9X-RAY DIFFRACTION9chain 'B' and (resid 110 through 141 )
10X-RAY DIFFRACTION10chain 'C' and (resid 137 through 158 )
11X-RAY DIFFRACTION11chain 'D' and (resid 136 through 157 )

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