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- PDB-9fky: Discovery of a Series of Covalent, Cell Active Bfl-1 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 9fky
TitleDiscovery of a Series of Covalent, Cell Active Bfl-1 Inhibitors
ComponentsBcl-2-related protein A1
KeywordsAPOPTOSIS / Bfl-1 / Bcl-2-related protein A1 / covalent
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
: / Bcl-2-related protein A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.557 Å
AuthorsHargreaves, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors.
Authors: Lucas, S.C.C. / Blackwell, J.H. / Borjesson, U. / Hargreaves, D. / Milbradt, A.G. / Bostock, M.J. / Ahmed, S. / Beaumont, K. / Cheung, T. / Demanze, S. / Gohlke, A. / Guerot, C. / Haider, A. ...Authors: Lucas, S.C.C. / Blackwell, J.H. / Borjesson, U. / Hargreaves, D. / Milbradt, A.G. / Bostock, M.J. / Ahmed, S. / Beaumont, K. / Cheung, T. / Demanze, S. / Gohlke, A. / Guerot, C. / Haider, A. / Kantae, V. / Kauffman, G.W. / Kinzel, O. / Kupcova, L. / Lainchbury, M.D. / Lamb, M.L. / Leon, L. / Palisse, A. / Sacchetto, C. / Storer, R.I. / Su, N. / Thomson, C. / Vales, J. / Chen, Y. / Hu, X.
History
DepositionJun 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,7774
Polymers34,8862
Non-polymers8912
Water1,874104
1
A: Bcl-2-related protein A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8882
Polymers17,4431
Non-polymers4451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bcl-2-related protein A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8882
Polymers17,4431
Non-polymers4451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.927, 43.200, 62.088
Angle α, β, γ (deg.)90.00, 93.66, 90.00
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.: 2
Source method: isolated from a genetically manipulated source
Details: Bfl-1 / Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2A1, BCL2L5, BFL1, GRS, HBPA1 / Production host: Escherichia (bacteria) / References: UniProt: Q16548
#2: Chemical ChemComp-A1IDP / ~{N}-[4-[(1~{R},3~{R})-3-azanylcyclopentyl]oxyphenyl]-~{N}-[(1~{S})-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl]propanamide


Mass: 445.477 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / 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: 2.18 Å3/Da / Density % sol: 43.68 %
Crystal growTemperature: 310 K / Method: vapor diffusion, sitting drop / Details: PCPT 0.1M pH 5, Na3 Cit 1.1M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.95374 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95374 Å / Relative weight: 1
ReflectionResolution: 1.557→61.962 Å / Num. obs: 31897 / % possible obs: 93.2 % / Redundancy: 5.1 % / CC1/2: 0.999 / Net I/σ(I): 5.1
Reflection shellResolution: 1.557→1.706 Å / Num. unique obs: 1595 / CC1/2: 0.508

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
BUSTER2.11.8 (24-FEB-2021)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.557→61.96 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.946 / SU R Cruickshank DPI: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.122 / SU Rfree Blow DPI: 0.114 / SU Rfree Cruickshank DPI: 0.116
RfactorNum. reflection% reflectionSelection details
Rfree0.2371 1653 5.19 %RANDOM
Rwork0.2097 ---
obs0.2111 31875 73.4 %-
Displacement parametersBiso mean: 28.54 Å2
Baniso -1Baniso -2Baniso -3
1--0.0785 Å20 Å2-0.563 Å2
2--0.3984 Å20 Å2
3----0.3199 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.557→61.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2388 0 64 104 2556
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082520HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.893416HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d902SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes462HARMONIC5
X-RAY DIFFRACTIONt_it2520HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion16.35
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion316SEMIHARMONIC5
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_contact2272SEMIHARMONIC4
LS refinement shellResolution: 1.56→1.66 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3408 -4.39 %
Rwork0.2767 610 -
all0.2794 638 -
obs--8.67 %

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