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- PDB-9giq: BFL1 covalently bound to inhibitor compound 13 -

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Basic information

Entry
Database: PDB / ID: 9giq
TitleBFL1 covalently bound to inhibitor compound 13
ComponentsBcl-2-related protein A1
KeywordsAPOPTOSIS / BFL / BCL / covalent / inhibitor
Function / homology
Function and homology information


Regulation of MITF-M-dependent genes involved in apoptosis / mitochondrial fusion / Nuclear events stimulated by ALK signaling in cancer / extrinsic apoptotic signaling pathway in absence of ligand / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / channel activity / mitochondrial outer membrane / positive regulation of apoptotic process / negative regulation of apoptotic process ...Regulation of MITF-M-dependent genes involved in apoptosis / mitochondrial fusion / Nuclear events stimulated by ALK signaling in cancer / extrinsic apoptotic signaling pathway in absence of ligand / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / channel activity / mitochondrial outer membrane / positive regulation of apoptotic process / negative regulation of apoptotic process / cytosol / cytoplasm
Similarity search - Function
Bcl-2-related protein A1 / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family ...Bcl-2-related protein A1 / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
: / (2S,3S)-butane-2,3-diol / Bcl-2-related protein A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.421 Å
AuthorsCottee, M.A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors.
Authors: Palisse, A. / Cheung, T. / Blokhuis, A. / Cogswell, T. / Martins, B.S. / Riemens, R. / Schellekens, R. / Battocchio, G. / Jansen, C. / Cottee, M.A. / Ornell, K. / Sacchetto, C. / Leon, L. / ...Authors: Palisse, A. / Cheung, T. / Blokhuis, A. / Cogswell, T. / Martins, B.S. / Riemens, R. / Schellekens, R. / Battocchio, G. / Jansen, C. / Cottee, M.A. / Ornell, K. / Sacchetto, C. / Leon, L. / van Hoek-Emmelot, M. / Bostock, M. / Brauer, B.L. / Beaumont, K. / Lucas, S.C.C. / Ahmed, S. / Blackwell, J.H. / Borjesson, U. / Gohlke, A. / Gramatikov, I.M.T. / Hargreaves, D. / van Hoeven, V. / Kantae, V. / Kupcova, L. / Milbradt, A.G. / Seneviratne, U. / Su, N. / Vales, J. / Wang, H. / White, M.J. / Kinzel, O.
History
DepositionAug 19, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2025Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bcl-2-related protein A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,9783
Polymers17,4431
Non-polymers5352
Water1,49583
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8300 Å2
Unit cell
Length a, b, c (Å)45.792, 43.386, 43.627
Angle α, β, γ (deg.)90, 114.54, 90
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Bcl-2-related protein A1 / Bcl-2-like protein 5 / Bcl2-L-5 / Hemopoietic-specific early response protein / Protein BFL-1 / Protein GRS


Mass: 17442.889 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2A1, BCL2L5, BFL1, GRS, HBPA1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 Gold / References: UniProt: Q16548
#2: Chemical ChemComp-BUD / (2S,3S)-butane-2,3-diol


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#3: Chemical ChemComp-A1ILV / ~{N}-[4-[(1~{R},3~{R})-3-azanylcyclopentyl]oxyphenyl]-~{N}-[(1~{S})-1-(4-chlorophenyl)-3-methyl-3-oxidanyl-butyl]propanamide


Mass: 444.994 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33ClN2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.26 Å3/Da / Density % sol: 38.3 % / Description: Angular plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: Protein:ligand complex at ~4mg/ml in 20 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 2 mM TCEP, 1%DMSO. 150nL mixed with 150nL of well solution, 0.1M PCPT* pH 9.50, Na3 Citrate 0.60 M. *PCPT = ...Details: Protein:ligand complex at ~4mg/ml in 20 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 2 mM TCEP, 1%DMSO. 150nL mixed with 150nL of well solution, 0.1M PCPT* pH 9.50, Na3 Citrate 0.60 M. *PCPT = Sodium propionate, sodium cacodylate trihydrate, bis-tris propane buffer system. Using STPLabtech Mosquito.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.98011 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 30, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 1.421→37.562 Å / Num. obs: 21747 / % possible obs: 73.7 % / Redundancy: 3.5 % / CC1/2: 0.995 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.075 / Rrim(I) all: 0.144 / Net I/σ(I): 9.9
Reflection shellResolution: 1.421→1.536 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.83 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1089 / CC1/2: 0.457 / Rpim(I) all: 0.524 / Rrim(I) all: 0.985 / % possible all: 17.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSJan 10, 2022data reduction
Aimless0.7.7data scaling
autoPROC20211020data processing
STARANISO20211020data scaling
PHASERccp4-8.0phasing
Coot0.9.8.83model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.421→37.56 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.898 / SU R Cruickshank DPI: 0.097 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.097 / SU Rfree Blow DPI: 0.1 / SU Rfree Cruickshank DPI: 0.1
RfactorNum. reflection% reflectionSelection details
Rfree0.2567 1039 -RANDOM
Rwork0.2163 ---
obs0.2183 21747 73.8 %-
Displacement parametersBiso mean: 15.2 Å2
Baniso -1Baniso -2Baniso -3
1-2.0851 Å20 Å2-0.6241 Å2
2---0.696 Å20 Å2
3----1.3891 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.421→37.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1185 0 37 83 1305
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111290HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.031756HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d456SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes223HARMONIC5
X-RAY DIFFRACTIONt_it1290HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion167SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1272SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion15.12
LS refinement shellResolution: 1.421→1.5 Å
RfactorNum. reflection% reflection
Rfree0.3096 18 -
Rwork0.2914 --
obs--10.47 %
Refinement TLS params.Origin x: 1.6268 Å / Origin y: -0.0133 Å / Origin z: 11.2202 Å
111213212223313233
T-0.0357 Å2-0.0232 Å2-0.0055 Å2--0.1281 Å2-0.0234 Å2---0.1217 Å2
L1.3545 °2-0.9024 °2-0.0479 °2-1.7815 °2-0.2574 °2--2.2608 °2
S0.0446 Å °0.0389 Å °0.1351 Å °0.0389 Å °-0.0265 Å °0.1013 Å °0.1351 Å °0.1013 Å °-0.0181 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A4 - 151
2X-RAY DIFFRACTION1{ A|* }A202

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