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- PDB-7zlp: Crystal structure of SOCS2:ElonginB:ElonginC in complex with comp... -

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Basic information

Entry
Database: PDB / ID: 7zlp
TitleCrystal structure of SOCS2:ElonginB:ElonginC in complex with compound 9
Components
  • Elongin-B
  • Elongin-C
  • Suppressor of cytokine signaling 2
KeywordsLIGASE / E3 ligase / suppressor of cytokine signaling
Function / homology
Function and homology information


JAK pathway signal transduction adaptor activity / negative regulation of receptor signaling pathway via JAK-STAT / 1-phosphatidylinositol-3-kinase regulator activity / target-directed miRNA degradation / elongin complex / VCB complex / phosphatidylinositol 3-kinase complex / growth hormone receptor binding / Cul5-RING ubiquitin ligase complex / growth hormone receptor signaling pathway ...JAK pathway signal transduction adaptor activity / negative regulation of receptor signaling pathway via JAK-STAT / 1-phosphatidylinositol-3-kinase regulator activity / target-directed miRNA degradation / elongin complex / VCB complex / phosphatidylinositol 3-kinase complex / growth hormone receptor binding / Cul5-RING ubiquitin ligase complex / growth hormone receptor signaling pathway / Cul2-RING ubiquitin ligase complex / negative regulation of multicellular organism growth / cell surface receptor signaling pathway via JAK-STAT / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / phosphatidylinositol phosphate biosynthetic process / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / regulation of signal transduction / Tat-mediated elongation of the HIV-1 transcript / mammary gland alveolus development / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Growth hormone receptor signaling / cellular response to hormone stimulus / Negative regulation of FLT3 / RNA Polymerase II Pre-transcription Events / lactation / positive regulation of neuron differentiation / Interleukin-7 signaling / transcription corepressor binding / transcription elongation by RNA polymerase II / regulation of cell growth / transcription initiation at RNA polymerase II promoter / Evasion by RSV of host interferon responses / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / insulin-like growth factor receptor binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Regulation of expression of SLITs and ROBOs / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / response to estradiol / protein-macromolecule adaptor activity / Neddylation / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / protein ubiquitination / intracellular signal transduction / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / nucleoplasm / cytosol / cytoplasm
Similarity search - Function
Suppressor of cytokine signalling 2 / SOCS2, SH2 domain / suppressors of cytokine signalling / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Elongin B / Elongin-C ...Suppressor of cytokine signalling 2 / SOCS2, SH2 domain / suppressors of cytokine signalling / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Elongin B / Elongin-C / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-JHR / PHOSPHATE ION / Suppressor of cytokine signaling 2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsRamachandran, S. / Ciulli, A. / Makukhin, N.
Funding supportEuropean Union, Switzerland, 2items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2012-StG-311460 DrugE3CRLsEuropean Union
Innovative Medicines Initiative875510 Switzerland
CitationJournal: Nat Commun / Year: 2023
Title: Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2.
Authors: Ramachandran, S. / Makukhin, N. / Haubrich, K. / Nagala, M. / Forrester, B. / Lynch, D.M. / Casement, R. / Testa, A. / Bruno, E. / Gitto, R. / Ciulli, A.
History
DepositionApr 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation / Item: _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Oct 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3May 1, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Suppressor of cytokine signaling 2
B: Elongin-B
C: Elongin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9955
Polymers43,3963
Non-polymers5992
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4650 Å2
ΔGint-50 kcal/mol
Surface area17620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.153, 52.282, 77.453
Angle α, β, γ (deg.)90.000, 108.447, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein Suppressor of cytokine signaling 2 / SOCS-2 / Cytokine-inducible SH2 protein 2 / CIS-2 / STAT-induced STAT inhibitor 2 / SSI-2


Mass: 19273.268 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOCS2, CIS2, SSI2, STATI2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14508
#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 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.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369

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Non-polymers , 3 types, 186 molecules

#4: Chemical ChemComp-JHR / [4-[(2~{S})-2-[2-(4-fluorophenyl)ethanoylamino]-3-[(4-fluorophenyl)methylamino]-3-oxidanylidene-propyl]phenyl] dihydrogen phosphate


Mass: 504.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23F2N2O6P / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.61 Å3/Da / Density % sol: 52.92 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 100mM Tris-bicine pH(6.5-7), PEG 8K(9-14%), Ethylene glycol (26-20%)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.94→53.28 Å / Num. obs: 31861 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 32.89 Å2 / Rmerge(I) obs: 0.196 / Rpim(I) all: 0.083 / Rrim(I) all: 0.214 / Net I/σ(I): 5.6
Reflection shellResolution: 1.94→1.99 Å / Num. unique obs: 2327 / CC1/2: 0.082

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
xia2data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: SBC

Resolution: 1.94→42.6 Å / SU ML: 0.2498 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.5086
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2401 1605 5.04 %
Rwork0.198 30210 -
obs0.2001 31815 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.32 Å2
Refinement stepCycle: LAST / Resolution: 1.94→42.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2841 0 40 184 3065
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00792941
X-RAY DIFFRACTIONf_angle_d0.95543984
X-RAY DIFFRACTIONf_chiral_restr0.0599453
X-RAY DIFFRACTIONf_plane_restr0.0079501
X-RAY DIFFRACTIONf_dihedral_angle_d8.2539400
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.94-20.31721650.27942632X-RAY DIFFRACTION97.56
2-2.070.31561560.25492726X-RAY DIFFRACTION99.93
2.07-2.150.28951580.24672704X-RAY DIFFRACTION99.86
2.15-2.250.27171540.23472722X-RAY DIFFRACTION99.76
2.25-2.370.26111410.21732742X-RAY DIFFRACTION99.86
2.37-2.520.24551480.22342747X-RAY DIFFRACTION99.97
2.52-2.710.2621380.22022746X-RAY DIFFRACTION100
2.71-2.990.25531200.21062786X-RAY DIFFRACTION99.97
2.99-3.420.23731430.2012753X-RAY DIFFRACTION100
3.42-4.310.22061490.1682802X-RAY DIFFRACTION99.97
4.31-42.60.20241330.17222850X-RAY DIFFRACTION99.87
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)
13.160793732750.1527857703190.03228870645044.63712884658-2.01332826384.003325380760.05912478762480.112064157552-0.07903040625980.000173028180063-0.160140236383-0.2063657569950.0008210591372190.160131117060.09804876919210.1389738510180.0202595478602-4.27033676695E-60.129367260102-0.02427200506990.19965555275812.3703689091-4.064623960628.545256026
24.552980986832.665534103711.241697018315.151821912741.802101270964.967627698240.0446132619606-0.202495883980.01961895676050.1117041373220.011276192331-0.06434628083040.0108264947675-0.127346875099-0.035312142720.2052533787010.006591058526460.0416077862780.156174630025-0.02778858018510.1939564264038.306115673015.2301409395536.4603684855
34.090221239742.7573831063-0.809734863393.75301496648-0.7156414393792.085639272010.186489235836-0.10976998120.1848916299140.391145301866-0.225451457780.247563235414-0.161835878603-0.1034132647170.02096445648340.2105840536350.00756343106008-0.01039398434020.196273312316-0.03563487173780.200835447856-4.15231683888-2.0221583282830.8056021173
42.306727748811.605532211620.01734635971752.98136059225-0.7344328722471.392187612540.1130758994820.882016521799-0.632381572802-0.02189146696690.248146522882-0.164548037342-0.1844553990280.524353114812-0.3674623764720.468863665099-0.121905024709-0.01434539725180.742539715975-0.2098506192730.333819567515-14.0386888713-14.42069255744.24171826337
53.25046042048-2.01786822859-1.720601818941.52223129053-0.003340644813418.276261781810.04930478381110.191446049895-0.0787171555438-0.492069676064-0.06552251471890.1514113730440.413405639467-0.1645690310910.01498781526690.482632065564-0.1470165464270.004406227629280.404115766168-0.09110880857450.330862251302-18.010740011-19.939982711-2.0353099586
67.21118552693-4.65674409213-5.282579844234.895541971511.411079560386.027773462990.07314890020280.0986552063880.477806330559-0.803226316377-0.00834733041796-0.232639319119-0.595091630293-0.598198349765-0.07394644492160.67498280174-0.123776942841-0.0001073434911170.506227181616-0.1145332944040.487436718949-16.8690289667-8.89305209565-7.00740336785
75.194105445171.21898828654-0.1585106621174.04145212205-0.07200725368475.29209617275-0.1645797253630.2040124418810.244140964469-0.3838110561480.191756386409-0.360348521656-1.307048022040.498385956458-0.05314845220780.593401139191-0.1057550163430.04553025659130.52311687557-0.114047741050.426709167875-9.61235625392-7.446438144355.99280397571
82.84267527971-0.349985117401-0.5337784436711.32836990927-0.9326262364060.9004113580010.05705515224330.4456953417310.105889794326-0.4619575971360.1840169185530.144424014736-0.154959701054-0.465138257687-0.2184274281120.279576052074-0.0695218413401-0.0255936632820.4048512752720.01903009660610.328855130866-26.4158271227-11.32046636210.099800145
97.36528529877-1.672547583461.906588835841.07345311590.1719853401535.519716318630.1287147114210.47459706299-0.797454694139-0.148239064905-0.02145201351440.1130850575480.915738717044-0.16079601531-0.1108376000120.425108802878-0.1119099921780.02251413942160.297066680538-0.09603067693180.422510203796-16.0033219373-26.585417412616.1167522792
105.713637281451.46757117928-0.3665656316264.582851828740.311635746033.94926244284-0.0987476803230.293544509588-0.0981070358687-0.07776677632180.156720719787-0.1780062219190.1507539186110.0597766840184-0.05127424913330.217947965057-0.0278301881679-0.002970122385480.215013753932-0.03900005441340.199459243333-12.2631600221-14.933469907520.3554805719
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 30 through 100 )AA30 - 1001 - 71
22chain 'A' and (resid 101 through 134 )AA101 - 13472 - 105
33chain 'A' and (resid 135 through 198 )AA135 - 198106 - 169
44chain 'B' and (resid 1 through 9 )BB1 - 91 - 9
55chain 'B' and (resid 10 through 45 )BB10 - 4510 - 45
66chain 'B' and (resid 46 through 60 )BB46 - 6046 - 60
77chain 'B' and (resid 61 through 72 )BB61 - 7261 - 72
88chain 'B' and (resid 73 through 104 )BB73 - 10473 - 104
99chain 'C' and (resid 16 through 58 )CC16 - 581 - 36
1010chain 'C' and (resid 59 through 112 )CC59 - 11237 - 90

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