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- PDB-7nd1: First-in-class small molecule inhibitors of Polycomb Repressive C... -

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Basic information

Entry
Database: PDB / ID: 7nd1
TitleFirst-in-class small molecule inhibitors of Polycomb Repressive Complex 1 (PRC1) RING domain
Components
  • E3 ubiquitin-protein ligase RING2
  • Polycomb complex protein BMI-1
KeywordsGENE REGULATION / Polycomb Repressive Complex 1 (PRC1) / Inhibitor
Function / homology
Function and homology information


histone H2AK119 ubiquitin ligase activity / PRC1 complex / regulation of kidney development / RING-like zinc finger domain binding / segment specification / rostrocaudal neural tube patterning / ubiquitin-protein transferase activator activity / somatic stem cell division / embryonic skeletal system morphogenesis / regulation of adaxial/abaxial pattern formation ...histone H2AK119 ubiquitin ligase activity / PRC1 complex / regulation of kidney development / RING-like zinc finger domain binding / segment specification / rostrocaudal neural tube patterning / ubiquitin-protein transferase activator activity / somatic stem cell division / embryonic skeletal system morphogenesis / regulation of adaxial/abaxial pattern formation / sex chromatin / PcG protein complex / positive regulation of immature T cell proliferation in thymus / SUMOylation of DNA methylation proteins / gastrulation with mouth forming second / SUMOylation of RNA binding proteins / anterior/posterior axis specification / positive regulation of ubiquitin-protein transferase activity / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression, epigenetic / Transcriptional Regulation by E2F6 / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / germ cell development / humoral immune response / hemopoiesis / MLL1 complex / negative regulation of apoptotic signaling pathway / cellular response to interleukin-1 / ubiquitin ligase complex / cellular response to dexamethasone stimulus / negative regulation of DNA-binding transcription factor activity / SUMOylation of DNA damage response and repair proteins / heterochromatin / positive regulation of B cell proliferation / SUMOylation of transcription cofactors / SUMOylation of chromatin organization proteins / epigenetic regulation of gene expression / Regulation of PTEN gene transcription / apoptotic signaling pathway / promoter-specific chromatin binding / euchromatin / brain development / RING-type E3 ubiquitin transferase / positive regulation of fibroblast proliferation / ubiquitin protein ligase activity / mitotic cell cycle / regulation of gene expression / Oxidative Stress Induced Senescence / gene expression / in utero embryonic development / protein ubiquitination / nuclear body / chromatin remodeling / chromatin binding / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
E3 ubiquitin-protein ligase RING2 / E3 ubiquitin-protein ligase RING1/RING2 / RAWUL domain / RAWUL domain RING finger- and WD40-associated ubiquitin-like / Zinc finger, C3HC4 type (RING finger) / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-U9E / Polycomb complex protein BMI-1 / E3 ubiquitin-protein ligase RING2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics
AuthorsCierpicki, T. / Lund, G. / Jaremko, L.
CitationJournal: Nat.Chem.Biol. / Year: 2021
Title: Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.
Authors: Shukla, S. / Ying, W. / Gray, F. / Yao, Y. / Simes, M.L. / Zhao, Q. / Miao, H. / Cho, H.J. / Gonzalez-Alonso, P. / Winkler, A. / Lund, G. / Purohit, T. / Kim, E. / Zhang, X. / Ray, J.M. / ...Authors: Shukla, S. / Ying, W. / Gray, F. / Yao, Y. / Simes, M.L. / Zhao, Q. / Miao, H. / Cho, H.J. / Gonzalez-Alonso, P. / Winkler, A. / Lund, G. / Purohit, T. / Kim, E. / Zhang, X. / Ray, J.M. / He, S. / Nikolaidis, C. / Ndoj, J. / Wang, J. / Jaremko, L. / Jaremko, M. / Ryan, R.J.H. / Guzman, M.L. / Grembecka, J. / Cierpicki, T.
History
DepositionJan 29, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 23, 2021Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase RING2
H: Polycomb complex protein BMI-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1217
Polymers24,4952
Non-polymers6265
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4640 Å2
ΔGint-29 kcal/mol
Surface area11230 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 200structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein E3 ubiquitin-protein ligase RING2 / Huntingtin-interacting protein 2-interacting protein 3 / HIP2-interacting protein 3 / Protein DinG ...Huntingtin-interacting protein 2-interacting protein 3 / HIP2-interacting protein 3 / Protein DinG / RING finger protein 1B / RING1b / RING finger protein 2 / RING finger protein BAP-1 / RING-type E3 ubiquitin transferase RING2


Mass: 12766.979 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RNF2, BAP1, DING, HIPI3, RING1B / Production host: Escherichia coli (E. coli)
References: UniProt: Q99496, RING-type E3 ubiquitin transferase
#2: Protein Polycomb complex protein BMI-1 / Polycomb group RING finger protein 4 / RING finger protein 51


Mass: 11727.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BMI1, PCGF4, RNF51 / Production host: Escherichia coli (E. coli) / References: UniProt: P35226
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-U9E / 3-(2-chlorophenyl)-4-ethyl-5-(1~{H}-indol-4-yl)-1~{H}-pyrrole-2-carboxylic acid


Mass: 364.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-15N TROSY
121isotropic13D HNCA
131isotropic13D HNCO
141isotropic13D HN(CA)CO
151isotropic13D HN(CO)CA
181isotropic13D HN(CA)CB
171isotropic13D CBCA(CO)NH
161isotropic13D 1H-15N NOESY
191isotropic13D 1H-13C NOESY aliphatic

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Sample preparation

DetailsType: solution
Contents: 0.12 mM [U-2H; U-13C; U-15N; CH3 ILV] Ring1B-BMI1, 95% H2O/5% D2O
Label: sample1 / Solvent system: 95% H2O/5% D2O
SampleConc.: 0.12 mM / Component: Ring1B-BMI1 / Isotopic labeling: [U-2H; U-13C; U-15N; CH3 ILV]
Sample conditionsDetails: 50 mM sodium phosphate, pH 6.8, 150 mM NaCl, 1 mM TCEP, 10 uM ZnCl2, 5% DMSO
Ionic strength: 150 mM / Label: conditions1 / pH: 6.8 / Pressure: 1 atm / Temperature: 303.3 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE III / Manufacturer: Bruker / Model: AVANCE III / Field strength: 600 MHz

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Processing

NMR software
NameVersionDeveloperClassification
HADDOCK2.4Bonvinrefinement
HADDOCKBonvinstructure calculation
SparkyGoddardchemical shift assignment
SparkyGoddardpeak picking
RefinementMethod: molecular dynamics / Software ordinal: 1
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 200 / Conformers submitted total number: 20

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