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- PDB-9e31: Discovery of Potent, Highly Selective and Efficacious SMARCA2 Deg... -

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Basic information

Entry
Database: PDB / ID: 9.0E+31
TitleDiscovery of Potent, Highly Selective and Efficacious SMARCA2 Degraders - Compound 6
ComponentsIsoform Short of Probable global transcription activator SNF2L2
KeywordsTRANSCRIPTION / Protein degrader
Function / homology
Function and homology information


bBAF complex / npBAF complex / nBAF complex / brahma complex / nucleosome array spacer activity / GBAF complex / regulation of G0 to G1 transition / intermediate filament cytoskeleton / regulation of nucleotide-excision repair / SWI/SNF complex ...bBAF complex / npBAF complex / nBAF complex / brahma complex / nucleosome array spacer activity / GBAF complex / regulation of G0 to G1 transition / intermediate filament cytoskeleton / regulation of nucleotide-excision repair / SWI/SNF complex / regulation of mitotic metaphase/anaphase transition / positive regulation of T cell differentiation / positive regulation of double-strand break repair / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / positive regulation of stem cell population maintenance / Regulation of MITF-M-dependent genes involved in pigmentation / regulation of G1/S transition of mitotic cell cycle / negative regulation of cell differentiation / spermatid development / ATP-dependent activity, acting on DNA / positive regulation of myoblast differentiation / positive regulation of cell differentiation / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / helicase activity / negative regulation of cell growth / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / RMTs methylate histone arginines / nervous system development / histone binding / transcription coactivator activity / hydrolase activity / transcription cis-regulatory region binding / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2-ATP coupling, chromatin remodelling complex / Snf2, ATP coupling domain ...BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2-ATP coupling, chromatin remodelling complex / Snf2, ATP coupling domain / Snf2-ATP coupling, chromatin remodelling complex / domain in helicases and associated with SANT domains / HSA domain / Helicase/SANT-associated domain / HSA domain profile. / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / Helicase conserved C-terminal domain / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / ACETATE ION / SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsStrickland, C. / Rice, C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.
Authors: Li, Z. / Harikrishnan, L.S. / Xu, G. / Samanta, D. / Clemente, J.C. / Leng, L. / Tu, W. / Yang, L. / Huang, L. / Wang, M. / Wang, S. / Deng, Q. / Behshad, E. / Nagilla, R. / Orth, P. / Rice, ...Authors: Li, Z. / Harikrishnan, L.S. / Xu, G. / Samanta, D. / Clemente, J.C. / Leng, L. / Tu, W. / Yang, L. / Huang, L. / Wang, M. / Wang, S. / Deng, Q. / Behshad, E. / Nagilla, R. / Orth, P. / Rice, C. / Strickland, C. / Mohammad, H.P. / Priestley, E.S. / Sui, Z.
History
DepositionOct 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform Short of Probable global transcription activator SNF2L2
B: Isoform Short of Probable global transcription activator SNF2L2
C: Isoform Short of Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,78112
Polymers43,1423
Non-polymers1,6409
Water3,513195
1
A: Isoform Short of Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9254
Polymers14,3811
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform Short of Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9254
Polymers14,3811
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Isoform Short of Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9314
Polymers14,3811
Non-polymers5513
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.030, 66.030, 88.810
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein Isoform Short of Probable global transcription activator SNF2L2 / ATP-dependent helicase SMARCA2 / BRG1-associated factor 190B / BAF190B / Protein brahma homolog / ...ATP-dependent helicase SMARCA2 / BRG1-associated factor 190B / BAF190B / Protein brahma homolog / hBRM / SNF2-alpha / SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2


Mass: 14380.542 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMARCA2, BAF190B, BRM, SNF2A, SNF2L2 / Production host: Escherichia coli (E. coli)
References: UniProt: P51531, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#2: Chemical ChemComp-A1A1P / (12'R)-4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-5'-one


Mass: 419.946 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H26ClN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.59 Å3/Da / Density % sol: 52.53 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.01 M ZnCl2 15% v/v PEG 6000 5.5% v/v ethylene glycol

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 19, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.96→48.08 Å / Num. obs: 31037 / % possible obs: 99.9 % / Redundancy: 10.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.179 / Rpim(I) all: 0.058 / Rrim(I) all: 0.188 / Χ2: 1.01 / Net I/σ(I): 9.2 / Num. measured all: 326807
Reflection shellResolution: 1.96→2.01 Å / % possible obs: 99.5 % / Redundancy: 10.5 % / Rmerge(I) obs: 1.195 / Num. measured all: 23120 / Num. unique obs: 2193 / CC1/2: 0.805 / Rpim(I) all: 0.384 / Rrim(I) all: 1.255 / Χ2: 0.96 / Net I/σ(I) obs: 2.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.96→48.08 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.927 / SU B: 4.045 / SU ML: 0.114 / Cross valid method: THROUGHOUT / ESU R: 0.167 / ESU R Free: 0.155 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23829 1354 4.4 %RANDOM
Rwork0.19471 ---
obs0.1966 29669 99.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.307 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å20 Å2
2---0 Å2-0 Å2
3---0.02 Å2
Refinement stepCycle: 1 / Resolution: 1.96→48.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2870 0 102 195 3167
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0123029
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162957
X-RAY DIFFRACTIONr_angle_refined_deg1.6331.8714090
X-RAY DIFFRACTIONr_angle_other_deg0.5361.796836
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4995349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.919524
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.04810578
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0820.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023435
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02664
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3312.7481407
X-RAY DIFFRACTIONr_mcbond_other2.332.7481406
X-RAY DIFFRACTIONr_mcangle_it3.2224.9181751
X-RAY DIFFRACTIONr_mcangle_other3.2214.9181752
X-RAY DIFFRACTIONr_scbond_it3.363.1411622
X-RAY DIFFRACTIONr_scbond_other3.3593.1411623
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.1815.5712340
X-RAY DIFFRACTIONr_long_range_B_refined6.28128.733706
X-RAY DIFFRACTIONr_long_range_B_other6.28128.723707
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.96→2.011 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 128 -
Rwork0.243 2181 -
obs--99.4 %

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