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- PDB-8vlb: Crystal structure of EloBC-VHL-CDO1 complex bound to compound 4 m... -

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Basic information

Entry
Database: PDB / ID: 8vlb
TitleCrystal structure of EloBC-VHL-CDO1 complex bound to compound 4 molecular glue
Components
  • Cysteine dioxygenase type 1
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsAPOPTOSIS / VHL / CDO1 / VHL-small molecule-CDO1 ternary complex / degradation
Function / homology
Function and homology information


sulfur amino acid biosynthetic process / Degradation of cysteine and homocysteine / taurine biosynthetic process / cysteine dioxygenase / cysteine dioxygenase activity / regulation of cellular response to hypoxia / L-cysteine catabolic process / cysteine metabolic process / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT ...sulfur amino acid biosynthetic process / Degradation of cysteine and homocysteine / taurine biosynthetic process / cysteine dioxygenase / cysteine dioxygenase activity / regulation of cellular response to hypoxia / L-cysteine catabolic process / cysteine metabolic process / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / response to glucagon / 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 / nickel cation binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / response to amino acid / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / response to glucocorticoid / negative regulation of TORC1 signaling / response to cAMP / RNA Polymerase II Pre-transcription Events / lactation / negative regulation of autophagy / transcription corepressor binding / Evasion by RSV of host interferon responses / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / ferrous iron binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / protein-macromolecule adaptor activity / Neddylation / Replication of the SARS-CoV-2 genome / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / DNA-binding transcription factor binding / response to ethanol / amyloid fibril formation / molecular adaptor activity / protein stabilization / protein ubiquitination / inflammatory response / negative regulation of cell population proliferation / negative regulation of gene expression / ubiquitin protein ligase binding / regulation of DNA-templated transcription / 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 / mitochondrion / proteolysis / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
Cysteine dioxygenase type I / Cysteine dioxygenase type I / 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 ...Cysteine dioxygenase type I / Cysteine dioxygenase type I / 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 / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / RmlC-like cupin domain superfamily / SKP1/BTB/POZ domain superfamily / RmlC-like jelly roll fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-3JF / CITRIC ACID / : / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B / Cysteine dioxygenase type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsShu, W. / Ma, X. / Tutter, A. / Buckley, D. / Golosov, A. / Michaud, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: A small molecule VHL molecular glue degrader for cysteine dioxygenase 1
Authors: Tutter, A. / Buckley, D. / Golosov, A. / Ma, X. / Shu, W. / Michaud, G.
History
DepositionJan 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
D: Cysteine dioxygenase type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,4857
Polymers65,7644
Non-polymers7213
Water905
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)116.440, 178.116, 104.166
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 4 types, 4 molecules ABCD

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


Mass: 18712.328 Da / Num. of mol.: 1
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: 13147.781 Da / Num. of mol.: 1
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.: 1
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 Cysteine dioxygenase type 1 / / Cysteine dioxygenase type I / CDO / CDO-I


Mass: 23060.955 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDO1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16878, cysteine dioxygenase

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Non-polymers , 4 types, 8 molecules

#5: Chemical ChemComp-3JF / N-acetyl-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide


Mass: 472.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N4O4S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CIT / CITRIC ACID / Citric acid


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#7: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 4.11 Å3/Da / Density % sol: 70.05 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: 0.2M SODIUM CITRATE, 0.1M BIS-TRIS-PROPANE PH 6.5, 20% PEG3350

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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 PILATUS3 2M / Detector: PIXEL / Date: Jul 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→97.46 Å / Num. obs: 23239 / % possible obs: 95.3 % / Redundancy: 6.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.171 / Net I/σ(I): 8.1
Reflection shellResolution: 2.9→3.08 Å / Redundancy: 6.9 % / Rmerge(I) obs: 2.397 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 3885 / CC1/2: 0.411 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→58.22 Å / SU ML: 0.46 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.71 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2581 1181 5.09 %
Rwork0.208 --
obs0.2105 23190 95.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→58.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4296 0 47 5 4348
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054455
X-RAY DIFFRACTIONf_angle_d0.8336043
X-RAY DIFFRACTIONf_dihedral_angle_d9.1223017
X-RAY DIFFRACTIONf_chiral_restr0.049660
X-RAY DIFFRACTIONf_plane_restr0.005805
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.0320.42561530.3822811X-RAY DIFFRACTION100
3.032-3.19190.36641560.32842842X-RAY DIFFRACTION100
3.1919-3.39180.30811640.28272859X-RAY DIFFRACTION100
3.3918-3.65370.33241330.24842258X-RAY DIFFRACTION82
3.6537-4.02130.26581330.2052396X-RAY DIFFRACTION87
4.0213-4.60290.19891390.16712889X-RAY DIFFRACTION100
4.6029-5.79840.21321520.17262923X-RAY DIFFRACTION100
5.7984-58.220.24391510.18683031X-RAY DIFFRACTION100
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)
10.12560.1552-0.05980.046-0.09350.07520.5259-0.5831.06270.51350.17150.5338-0.7702-0.3883-0.00410.88240.03780.1520.688-0.07260.976669.217256.179616.5856
20.49540.10170.23790.0634-0.14540.71470.0071-0.1306-0.4506-0.18270.2853-1.4415-0.12450.54310.020.6096-0.1796-0.02630.4589-0.08630.635665.254138.992225.5405
31.38570.0639-0.09610.2049-0.4051.62440.133-0.0117-0.0649-0.09430.1554-0.1756-0.08560.2958-0.00080.5577-0.03680.03890.4741-0.00180.557470.368241.297517.6766
40.29660.5982-0.02661.1069-0.86660.9913-0.15620.2762-0.19190.60980.40550.50810.4372-0.09760.0030.65520.13610.01060.6769-0.0730.571762.638140.88615.8969
50.0034-0.69610.78290.3475-0.42470.6220.3322-0.166-0.2346-0.2978-0.38740.1543-0.7028-0.4622-0.00230.6611-0.0521-0.02070.4896-0.10380.645260.163433.458613.1209
60.2070.12190.06250.37730.22930.1503-0.05740.0936-0.1163-0.01640.2507-1.0284-0.4442-0.010.00140.88240.06520.05081.0747-0.12170.784867.544426.1818-7.2191
70.48980.05710.58950.0846-0.160.88670.0581-0.08890.155-0.8790.36670.8093-0.12571.7004-0.00221.0358-0.0010.05060.79960.19780.738961.082548.02183.7383
80.826-0.32360.18360.7898-0.34760.17640.0296-0.459-0.03720.2142-0.42540.5760.3947-0.39210.00030.7719-0.11060.10290.7584-0.20790.865836.674212.752213.0816
90.4256-0.1384-0.26770.34610.39230.3740.259-0.0434-0.60130.9076-0.25370.80650.5927-0.66440.00481.1363-0.12450.15330.87690.03321.036934.78994.152316.9844
100.50560.0897-0.52390.5825-0.46920.46790.0839-0.45-0.47290.6028-0.2103-0.30730.3267-0.2058-0.00040.8441-0.14020.04240.5616-0.04480.921739.33376.09612.1041
110.09360.3583-0.13150.16880.3288-0.25530.10010.5123-0.665-0.4276-0.0554-0.33790.78820.3519-0.00140.75330.12790.06940.8506-0.06071.081959.01579.1648-2.4911
120.18550.1567-0.00590.2365-0.28650.25150.17860.4067-0.54560.2391-0.78130.95410.2364-0.5074-0.00110.8334-0.0685-0.03020.7419-0.09770.840139.122115.779-1.7715
130.04870.2807-0.09010.3203-0.17560.35210.09850.11630.11930.11270.06110.85320.0244-0.5294-0.00090.67350.0807-0.1030.5677-0.1370.708739.699425.5990.0378
140.13270.2783-0.16440.5726-0.18390.43610.5090.6893-0.0888-0.8965-0.32610.48440.0172-0.6632-0.00520.73480.1271-0.09990.9553-0.08350.915835.341121.8366-7.603
150.98190.3707-0.2662-0.04270.02140.5591-0.337-0.11580.00460.02820.26150.1719-0.08060.21220.00010.69360.0818-0.05860.5155-0.10550.722350.917623.44089.0364
160.1050.0592-0.0473-0.0086-0.11740.2658-0.32431.5002-0.20810.0644-0.372-0.2858-0.6302-0.46420.00160.68590.133-0.02510.7575-0.08840.724755.077621.5245-3.8575
17-0.01490.12740.08310.20250.07750.27810.040.70550.26-0.43960.17650.5177-0.08170.38670.00010.8696-0.13720.03280.5976-0.02760.632494.673563.119315.7359
180.0319-0.04870.06760.0775-0.17590.19340.45450.34230.4960.6253-0.44880.194-0.54190.2198-0.00271.0874-0.360.07140.9401-0.11180.8823101.56161.506423.4499
191.04870.15590.41420.1406-0.06950.24340.50630.1676-0.16380.1878-0.20810.8687-0.2120.40090.00320.7431-0.13450.01030.7417-0.05040.86283.00448.296919.6103
200.2512-0.14870.0190.1675-0.11760.01950.5532-0.0898-0.0428-0.1039-0.0120.0245-0.18170.64730.00140.5657-0.14540.08760.9904-0.0370.609894.030748.003216.487
210.14320.0650.0063-0.11640.24520.34650.57870.6337-0.72740.17740.1885-0.79040.37540.6686-0.00160.71060.056-0.05971.4831-0.01771.334795.988841.461128.3139
220.17990.0424-0.07920.13480.42610.43440.1809-1.913-0.33240.449-0.0440.2079-0.61220.15470.00370.7497-0.0602-0.02551.3775-0.08160.753492.817449.981330.2774
230.54590.0578-0.0041.42080.52260.1426-0.93351.98890.1302-0.5382-0.8335-0.56540.0865-0.29770.06280.89170.0454-0.36621.57880.24041.2202106.757135.649940.3963
240.45820.36910.29610.21270.18990.1553-0.1318-1.47440.16031.43740.71810.3799-1.38020.57780.08421.259-0.15960.03541.22040.09290.687893.425652.391834.7693
251.3581-0.8397-0.69971.98740.42640.65890.2132-0.8646-0.35250.461-0.0709-0.38770.1840.10560.53440.8165-0.1573-0.14751.2194-0.01210.73196.893741.590928.9425
260.80970.34050.04250.609-0.16520.3128-1.15991.0568-0.1135-1.04190.60280.07541.2205-0.2153-0.01771.0526-0.18560.09081.1633-0.18930.867289.448740.174512.5864
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 61 through 70 )
2X-RAY DIFFRACTION2chain 'A' and (resid 71 through 79 )
3X-RAY DIFFRACTION3chain 'A' and (resid 80 through 121 )
4X-RAY DIFFRACTION4chain 'A' and (resid 122 through 141 )
5X-RAY DIFFRACTION5chain 'A' and (resid 142 through 167 )
6X-RAY DIFFRACTION6chain 'A' and (resid 168 through 193 )
7X-RAY DIFFRACTION7chain 'A' and (resid 194 through 208 )
8X-RAY DIFFRACTION8chain 'B' and (resid 1 through 35 )
9X-RAY DIFFRACTION9chain 'B' and (resid 36 through 60 )
10X-RAY DIFFRACTION10chain 'B' and (resid 61 through 89 )
11X-RAY DIFFRACTION11chain 'B' and (resid 90 through 104 )
12X-RAY DIFFRACTION12chain 'C' and (resid 17 through 27 )
13X-RAY DIFFRACTION13chain 'C' and (resid 28 through 47 )
14X-RAY DIFFRACTION14chain 'C' and (resid 48 through 66 )
15X-RAY DIFFRACTION15chain 'C' and (resid 67 through 96 )
16X-RAY DIFFRACTION16chain 'C' and (resid 97 through 112 )
17X-RAY DIFFRACTION17chain 'D' and (resid 6 through 24 )
18X-RAY DIFFRACTION18chain 'D' and (resid 25 through 39 )
19X-RAY DIFFRACTION19chain 'D' and (resid 40 through 58 )
20X-RAY DIFFRACTION20chain 'D' and (resid 59 through 77 )
21X-RAY DIFFRACTION21chain 'D' and (resid 78 through 91 )
22X-RAY DIFFRACTION22chain 'D' and (resid 92 through 107 )
23X-RAY DIFFRACTION23chain 'D' and (resid 108 through 118 )
24X-RAY DIFFRACTION24chain 'D' and (resid 119 through 133 )
25X-RAY DIFFRACTION25chain 'D' and (resid 134 through 178 )
26X-RAY DIFFRACTION26chain 'D' and (resid 179 through 190 )

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