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- PDB-6sis: Crystal structure of macrocyclic PROTAC 1 in complex with the sec... -

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Basic information

Entry
Database: PDB / ID: 6sis
TitleCrystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:ElonginC:ElonginB
Components
  • Bromodomain-containing protein 4
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTAC COMPLEX / MACROCYCLE / TARGETED DEGRADATION
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RNA polymerase II C-terminal domain binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of DNA damage checkpoint / P-TEFb complex binding / ubiquitin-like ligase-substrate adaptor activity / negative regulation by host of viral transcription / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / negative regulation of autophagy / RNA polymerase II CTD heptapeptide repeat kinase activity / transcription corepressor binding / condensed nuclear chromosome / transcription elongation by RNA polymerase II / positive regulation of cell differentiation / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / Vif-mediated degradation of APOBEC3G / lysine-acetylated histone binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / protein-macromolecule adaptor activity / chromosome / Neddylation / Replication of the SARS-CoV-2 genome / regulation of inflammatory response / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / positive regulation of canonical NF-kappaB signal transduction / amyloid fibril formation / Potential therapeutics for SARS / molecular adaptor activity / transcription coactivator activity / protein stabilization / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / mitochondrion / proteolysis / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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 ...von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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 B / Elongin-C / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / SKP1/BTB/POZ domain superfamily / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Bromodomain-like / Histone Acetyltransferase; Chain A / Ubiquitin-like (UB roll) / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin family / Bromodomain / Ubiquitin homologues / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / Up-down Bundle / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-LFE / Bromodomain-containing protein 4 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsHughes, S.J. / Testa, A. / Ciulli, A.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2020
Title: Structure-Based Design of a Macrocyclic PROTAC.
Authors: Testa, A. / Hughes, S.J. / Lucas, X. / Wright, J.E. / Ciulli, A.
History
DepositionAug 10, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: 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.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
E: Bromodomain-containing protein 4
F: Elongin-B
G: Elongin-C
H: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,21310
Polymers112,9718
Non-polymers2,2422
Water1267
1
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6065
Polymers56,4864
Non-polymers1,1211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Bromodomain-containing protein 4
F: Elongin-B
G: Elongin-C
H: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6065
Polymers56,4864
Non-polymers1,1211
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.459, 99.459, 148.426
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21E
12B
22F
13C
23G
14D
24H

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSASPASPAA349 - 45919 - 129
21LYSLYSASPASPEE349 - 45919 - 129
12METMETLYSLYSBB1 - 1041 - 104
22METMETLYSLYSFF1 - 1041 - 104
13METMETCYSCYSCC16 - 1121 - 97
23METMETCYSCYSGG16 - 1121 - 97
14PROPROGLNGLNDD61 - 20910 - 158
24PROPROGLNGLNHH61 - 20910 - 158

NCS ensembles :
ID
1
2
3
4

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Components

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Protein , 4 types, 8 molecules AEBFCGDH

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15060.332 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PNIC28a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#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 / Plasmid: pCDFDUET-1 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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: 10974.616 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Plasmid: pCDFDUET-1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#4: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Plasmid: PHAT4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337

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Non-polymers , 2 types, 9 molecules

#5: Chemical ChemComp-LFE / ~{N}-[(5~{S},7~{R},11~{S},23~{S})-11-~{tert}-butyl-34-(4-methyl-1,3-thiazol-5-yl)-7-oxidanyl-4,10,13-tris(oxidanylidene)-15,18,21,25,28,31-hexaoxa-3,9,12-triazatricyclo[30.4.0.0^{5,9}]hexatriaconta-1(32),33,35-trien-23-yl]-2-[(7~{S},9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,10,12-tetraen-9-yl]ethanamide


Mass: 1120.770 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C54H70ClN9O11S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.75 Å3/Da / Density % sol: 67.22 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10% (w/v) PEG 8000, 0.1 M Tris-HCl (pH 7.5) and 0.1 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.975 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.975 Å / Relative weight: 1
ReflectionResolution: 3.5→49.73 Å / Num. obs: 19211 / % possible obs: 92.6 % / Redundancy: 2.6 % / CC1/2: 0.984 / Rmerge(I) obs: 0.16 / Rpim(I) all: 0.109 / Rrim(I) all: 0.194 / Net I/σ(I): 4.5
Reflection shell

Diffraction-ID: 1 / Redundancy: 2.6 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.5-3.830.6941124243960.5430.480.849188.4
8.57-49.730.041349413190.9940.0280.05114.392.4

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Processing

Software
NameVersionClassification
Aimless0.7.1data scaling
REFMAC5.8.0230refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5T35

5t35


Resolution: 3.5→49.73 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.906 / SU B: 87.198 / SU ML: 0.56 / SU R Cruickshank DPI: 0.5358 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.573
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2468 940 4.9 %RANDOM
Rwork0.2195 ---
obs0.2208 18245 92.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.1 Å
Displacement parametersBiso max: 184.64 Å2 / Biso mean: 105.444 Å2 / Biso min: 28.22 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å2-0.06 Å2-0 Å2
2---0.12 Å2-0 Å2
3---0.41 Å2
Refinement stepCycle: final / Resolution: 3.5→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7208 0 154 7 7369
Biso mean--89.78 36.71 -
Num. residues----902
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0147546
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176761
X-RAY DIFFRACTIONr_angle_refined_deg0.7291.69310241
X-RAY DIFFRACTIONr_angle_other_deg0.6341.65615869
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9165892
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.65921.788397
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.367151264
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4381554
X-RAY DIFFRACTIONr_chiral_restr0.0280.2966
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.028334
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021352
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A36360.02
12E36360.02
21B31440.04
22F31440.04
31C26650.04
32G26650.04
41D47980.02
42H47980.02
LS refinement shellResolution: 3.5→3.913 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.33 259 -
Rwork0.321 4633 -
all-4892 -
obs--83.21 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.94161.4419-0.08886.8247-0.73672.1394-0.03410.00430.4345-0.1778-0.09070.3863-0.35960.27030.12480.6235-0.104-0.04690.4786-0.06630.262774.0097131.543713.4625
21.5743-0.98812.242.322-1.54255.5420.21170.0159-0.0992-0.0172-0.06050.2899-0.0354-0.3224-0.15120.4572-0.1053-0.00480.5758-0.01650.03737.995981.2529-17.1081
33.2735-0.6886-0.61616.55482.11594.82170.11840.2711-0.42-0.0987-0.0472-0.16870.61160.0391-0.07120.5169-0.0645-0.07920.4248-0.00980.073651.741975.882-7.3514
43.95052.1077-0.31025.2343-0.5631.31630.1765-0.1265-0.28790.242-0.1878-0.45690.06720.24760.01130.5108-0.0369-0.02850.45880.01470.044765.090493.87928.5999
55.0589-2.1748-0.43923.52970.4142.2274-0.11430.0917-0.50780.06090.1005-0.20280.09480.19480.01380.3875-0.11040.04910.74880.06310.139986.184187.9526-18.5113
60.84390.6735-0.53013.3367-1.68760.97820.23740.18080.41720.20210.15790.7505-0.1792-0.4116-0.39530.78480.26540.20061.40450.18840.777328.8449114.70519.2134
70.6823-1.4864-0.38015.67730.91770.36530.16130.03720.50570.10880.00110.1409-0.3231-0.3482-0.16250.91250.25650.10511.01870.0351.074538.9738126.4150.2271
83.5629-1.4360.04055.0537-0.52481.24870.19150.23110.8988-0.1218-0.0917-0.1291-0.4306-0.153-0.09980.62610.02440.08860.70640.16490.259160.0815117.0813-14.8003
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A349 - 459
2X-RAY DIFFRACTION2B1 - 104
3X-RAY DIFFRACTION3C16 - 112
4X-RAY DIFFRACTION4D61 - 209
5X-RAY DIFFRACTION5E349 - 459
6X-RAY DIFFRACTION6F1 - 104
7X-RAY DIFFRACTION7G16 - 112
8X-RAY DIFFRACTION8H61 - 209

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