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- PDB-9aqz: Crystal structure of Bcl-xL in complex with a small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 9aqz
TitleCrystal structure of Bcl-xL in complex with a small molecule inhibitor
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS / Bcl-xL / inhibitor
Function / homology
Function and homology information


apoptotic process in bone marrow cell / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of dendritic cell apoptotic process / negative regulation of execution phase of apoptosis ...apoptotic process in bone marrow cell / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of dendritic cell apoptotic process / negative regulation of execution phase of apoptosis / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / fertilization / regulation of growth / regulation of mitochondrial membrane permeability / Bcl-2 family protein complex / BH domain binding / NFE2L2 regulating tumorigenic genes / response to cycloheximide / cellular response to alkaloid / STAT5 activation downstream of FLT3 ITD mutants / hepatocyte apoptotic process / negative regulation of release of cytochrome c from mitochondria / negative regulation of reproductive process / negative regulation of developmental process / BH3 domain binding / germ cell development / apoptotic mitochondrial changes / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ectopic germ cell programmed cell death / negative regulation of protein localization to plasma membrane / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / ovarian follicle development / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / regulation of cytokinesis / epithelial cell proliferation / response to cytokine / regulation of mitochondrial membrane potential / cellular response to amino acid stimulus / cellular response to gamma radiation / synaptic vesicle membrane / endocytosis / RAS processing / male gonad development / intrinsic apoptotic signaling pathway in response to DNA damage / spermatogenesis / nuclear membrane / Interleukin-4 and Interleukin-13 signaling / defense response to virus / neuron apoptotic process / in utero embryonic development / negative regulation of neuron apoptotic process / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / centrosome / negative regulation of apoptotic process / protein kinase binding / endoplasmic reticulum / mitochondrion / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2 family BH4 motif signature. / Apoptosis regulator, Bcl-2 protein, BH4 / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH4 motif profile. / BH4 Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. ...Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2 family BH4 motif signature. / Apoptosis regulator, Bcl-2 protein, BH4 / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH4 motif profile. / BH4 Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / 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-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.961 Å
AuthorsJudge, R.A. / Judd, A.S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Adv / Year: 2024
Title: BCL-X L -targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.
Authors: Judd, A.S. / Bawa, B. / Buck, W.R. / Tao, Z.F. / Li, Y. / Mitten, M.J. / Bruncko, M. / Catron, N. / Doherty, G. / Durbin, K.R. / Enright, B. / Frey, R. / Haasch, D. / Haman, S. / Haight, A.R. ...Authors: Judd, A.S. / Bawa, B. / Buck, W.R. / Tao, Z.F. / Li, Y. / Mitten, M.J. / Bruncko, M. / Catron, N. / Doherty, G. / Durbin, K.R. / Enright, B. / Frey, R. / Haasch, D. / Haman, S. / Haight, A.R. / Henriques, T.A. / Holms, J. / Izeradjene, K. / Judge, R.A. / Jenkins, G.J. / Kunzer, A. / Leverson, J.D. / Martin, R.L. / Mitra, D. / Mittelstadt, S. / Nelson, L. / Nimmer, P. / Palma, J. / Peterson, R. / Phillips, D.C. / Ralston, S.L. / Rosenberg, S.H. / Shen, X. / Song, X. / Vaidya, K.R. / Wang, X. / Wang, J. / Xiao, Y. / Zhang, H. / Zhang, X. / Blomme, E.A. / Boghaert, E.R. / Kalvass, J.C. / Phillips, A. / Souers, A.J.
History
DepositionFeb 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Database references / Category: citation / Item: _citation.journal_issue

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,5734
Polymers18,6901
Non-polymers8843
Water1,53185
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.031, 78.389, 144.774
Angle α, β, γ (deg.)90, 90, 90
Int Tables number24
Space group name H-MI212121
Components on special symmetry positions
IDModelComponents
11A-450-

HOH

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Components

#1: Protein Bcl-2-like protein 1 / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 18689.816 Da / Num. of mol.: 1 / Mutation: W24A,E158K,D189A
Source method: isolated from a genetically manipulated source
Details: The following clone was used for structure studies [Bcl-xL (1-25)-GGGGGGG-(83-209) W24A, E158K, D189A]-LE-6His. In this form of the protein, an extended loop, residues 26-82 has been deleted ...Details: The following clone was used for structure studies [Bcl-xL (1-25)-GGGGGGG-(83-209) W24A, E158K, D189A]-LE-6His. In this form of the protein, an extended loop, residues 26-82 has been deleted and replaced with seven glycine residues. Point mutations are listed above.,The following clone was used for structure studies [Bcl-xL (1-25)-GGGGGGG-(83-209) W24A, E158K, D189A]-LE-6His. In this form of the protein, an extended loop, residues 26-82 has been deleted and replaced with seven glycine residues. Point mutations are listed above.
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Production host: Escherichia phage EcSzw-2 (virus) / References: UniProt: Q07817
#2: Chemical ChemComp-A1AFG / (3M)-3-(1-{[(1r,3R,5S,7r)-adamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic acid


Mass: 658.812 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H38N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cd
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 85 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.51 Å3/Da / Density % sol: 50.94 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7.5
Details: 1 M sodium acetate, 0.1 M HEPES pH 7.5, 0.05 M cadmium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.961→72.387 Å / Num. obs: 13959 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.998 / Net I/σ(I): 11.9
Reflection shellResolution: 1.961→1.995 Å / Num. unique obs: 672 / CC1/2: 0.9

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
autoPROCdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.961→72.39 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.177 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.186 / SU Rfree Blow DPI: 0.158 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.2644 676 -RANDOM
Rwork0.2429 ---
obs0.2439 13959 99.9 %-
Displacement parametersBiso mean: 38.27 Å2
Baniso -1Baniso -2Baniso -3
1-6.8014 Å20 Å20 Å2
2---11.823 Å20 Å2
3---5.0216 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 1.961→72.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1110 0 50 85 1245
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081191HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.781619HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d406SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes238HARMONIC5
X-RAY DIFFRACTIONt_it1191HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion137SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact991SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.27
X-RAY DIFFRACTIONt_other_torsion15.09
LS refinement shellResolution: 1.961→1.995 Å
RfactorNum. reflection% reflection
Rfree0.2715 18 -
Rwork0.3032 --
obs--98.61 %

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