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- PDB-9d4b: Discovery of SMD-3236, a Potent, Highly Selective and Efficacious... -

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Basic information

Entry
Database: PDB / ID: 9d4b
TitleDiscovery of SMD-3236, a Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers
Components
  • Elongin-B
  • Elongin-C
  • Probable global transcription activator SNF2L2
  • von Hippel-Lindau disease tumor suppressor
KeywordsTRANSCRIPTION / Cancer / Protein Degrader
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / RSC-type complex / elongin complex / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / RSC-type complex / elongin complex / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / SUMOylation of ubiquitinylation proteins / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of transcription elongation by RNA polymerase II / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / Tat-mediated elongation of the HIV-1 transcript / negative regulation of signal transduction / Formation of HIV-1 elongation complex containing HIV-1 Tat / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / protein serine/threonine kinase binding / transcription corepressor binding / Vif-mediated degradation of APOBEC3G / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / Inactivation of CSF3 (G-CSF) signaling / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Regulation of expression of SLITs and ROBOs / cell morphogenesis / ubiquitin-protein transferase activity / Antigen processing: Ubiquitination & Proteasome degradation / transcription corepressor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / regulation of gene expression / microtubule cytoskeleton / Replication of the SARS-CoV-2 genome / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / cellular response to hypoxia / molecular adaptor activity / DNA-binding transcription factor binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / protein ubiquitination / protein stabilization / cilium / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / enzyme binding / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / mitochondrion / proteolysis / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
Remodelling complex subunit Rsc/polybromo / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Elongin-C ...Remodelling complex subunit Rsc/polybromo / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Elongin-C / Elongin B / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsStrickland, C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: To Be Published
Title: Discovery of SMD-3236, a Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers
Authors: Strickland, C.
History
DepositionAug 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
E: Elongin-B
F: Elongin-C
G: Probable global transcription activator SNF2L2
H: Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,36710
Polymers111,1758
Non-polymers2,1922
Water00
1
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
G: Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,6835
Polymers55,5884
Non-polymers1,0961
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: von Hippel-Lindau disease tumor suppressor
E: Elongin-B
F: Elongin-C
H: Probable global transcription activator SNF2L2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,6835
Polymers55,5884
Non-polymers1,0961
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.130, 132.010, 210.700
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18615.215 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 11748.406 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#3: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10843.420 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#4: Protein Probable global transcription activator SNF2L2 / cDNA FLJ61143 / highly similar to Probable global transcription activator SNF2L2


Mass: 14380.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMARCA2 / Production host: Escherichia coli (E. coli) / References: UniProt: B4DNT1
#5: Chemical ChemComp-A1A1U / (4R)-1-[(2S)-2-{4-[(1S,4S)-4-({4-[(12'S)-4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl]piperidin-1-yl}methyl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-(morpholin-4-yl)ethyl]-L-prolinamide


Mass: 1095.830 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C61H75ClN10O5S / Feature type: SUBJECT OF INVESTIGATION
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: 2.91 Å3/Da / Density % sol: 57.77 %
Crystal growTemperature: 281.15 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.25 M Calcium acetate 0.1 M Sodium cacodylate pH 5.5 8% w/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→48.1 Å / Num. obs: 19935 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 0.994 / Rmerge(I) obs: 0.285 / Rpim(I) all: 0.079 / Rrim(I) all: 0.296 / Χ2: 1 / Net I/σ(I): 10.4 / Num. measured all: 269614
Reflection shellResolution: 3.3→3.56 Å / % possible obs: 100 % / Redundancy: 13.1 % / Rmerge(I) obs: 1.2 / Num. measured all: 53265 / Num. unique obs: 4058 / CC1/2: 0.812 / Rpim(I) all: 0.342 / Rrim(I) all: 1.248 / Χ2: 0.96 / Net I/σ(I) obs: 2.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0403refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.3→48.1 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.86 / SU B: 29.228 / SU ML: 0.475 / Cross valid method: THROUGHOUT / ESU R Free: 0.601 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.28581 1014 5.1 %RANDOM
Rwork0.20734 ---
obs0.21124 18919 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.343 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å2-0 Å20 Å2
2--0.55 Å20 Å2
3----0.41 Å2
Refinement stepCycle: 1 / Resolution: 3.3→48.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7272 0 156 0 7428
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0127604
X-RAY DIFFRACTIONr_bond_other_d0.0010.0167338
X-RAY DIFFRACTIONr_angle_refined_deg1.3851.67110316
X-RAY DIFFRACTIONr_angle_other_deg0.431.57216950
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0045890
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.539566
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.6101342
X-RAY DIFFRACTIONr_chiral_restr0.0620.21154
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028698
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021704
X-RAY DIFFRACTIONr_mcbond_it7.1717.6183590
X-RAY DIFFRACTIONr_mcbond_other7.1717.6183590
X-RAY DIFFRACTIONr_mcangle_it11.37413.6694470
X-RAY DIFFRACTIONr_mcangle_other11.37313.674471
X-RAY DIFFRACTIONr_scbond_it7.0898.0224014
X-RAY DIFFRACTIONr_scbond_other7.0888.0244015
X-RAY DIFFRACTIONr_scangle_other11.4614.4825847
X-RAY DIFFRACTIONr_long_range_B_refined15.95274.858538
X-RAY DIFFRACTIONr_long_range_B_other15.95174.868539
LS refinement shellResolution: 3.3→3.385 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 83 -
Rwork0.269 1360 -
obs--100 %

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