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- PDB-6xog: Structure of SUMO1-ML786519 adduct bound to SAE -

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Basic information

Entry
Database: PDB / ID: 6xog
TitleStructure of SUMO1-ML786519 adduct bound to SAE
Components
  • (SUMO-activating enzyme subunit ...) x 2
  • Small ubiquitin-related modifier 1
KeywordsLIGASE/LIGASE inhibitor / SAE / SUMO1 / covalent inhibitor / LIGASE / LIGASE-LIGASE inhibitor complex
Function / homology
Function and homology information


SUMO activating enzyme activity / SUMO activating enzyme complex / ubiquitin activating enzyme activity / protein localization to nuclear pore / negative regulation of transcription by transcription factor localization / SUMOylation of nuclear envelope proteins / SUMO is proteolytically processed / Negative regulation of activity of TFAP2 (AP-2) family transcription factors / negative regulation of delayed rectifier potassium channel activity / SUMO is conjugated to E1 (UBA2:SAE1) ...SUMO activating enzyme activity / SUMO activating enzyme complex / ubiquitin activating enzyme activity / protein localization to nuclear pore / negative regulation of transcription by transcription factor localization / SUMOylation of nuclear envelope proteins / SUMO is proteolytically processed / Negative regulation of activity of TFAP2 (AP-2) family transcription factors / negative regulation of delayed rectifier potassium channel activity / SUMO is conjugated to E1 (UBA2:SAE1) / negative regulation of potassium ion transmembrane transporter activity / PML body organization / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / nuclear stress granule / SUMO binding / positive regulation of protein sumoylation / small protein activating enzyme binding / negative regulation of action potential / SUMOylation of DNA methylation proteins / SUMOylation of immune response proteins / regulation of calcium ion transmembrane transport / XY body / SUMOylation of SUMOylation proteins / ATP-dependent protein binding / Maturation of nucleoprotein / SUMOylation of RNA binding proteins / regulation of cardiac muscle cell contraction / Transferases; Acyltransferases; Aminoacyltransferases / Postmitotic nuclear pore complex (NPC) reformation / negative regulation of DNA binding / positive regulation of protein targeting to mitochondrion / Maturation of nucleoprotein / ubiquitin-like protein conjugating enzyme binding / negative regulation of protein import into nucleus / SUMOylation of ubiquitinylation proteins / cellular response to cadmium ion / ubiquitin-specific protease binding / transcription factor binding / roof of mouth development / ubiquitin-like protein ligase binding / SUMOylation of transcription factors / protein sumoylation / SUMOylation of DNA replication proteins / postsynaptic cytosol / potassium channel regulator activity / Regulation of IFNG signaling / nuclear pore / presynaptic cytosol / SUMOylation of DNA damage response and repair proteins / Transcriptional and post-translational regulation of MITF-M expression and activity / SUMOylation of transcription cofactors / SUMOylation of chromatin organization proteins / enzyme activator activity / negative regulation of DNA-binding transcription factor activity / SUMOylation of intracellular receptors / positive regulation of protein-containing complex assembly / PKR-mediated signaling / PML body / Formation of Incision Complex in GG-NER / protein tag activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of protein localization / transferase activity / cellular response to heat / nuclear membrane / protein stabilization / nuclear speck / nuclear body / protein heterodimerization activity / DNA repair / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / nucleolus / glutamatergic synapse / enzyme binding / magnesium ion binding / RNA binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
SUMO-activating enzyme subunit 2, C-terminal domain / SUMO-activating enzyme subunit 2 C-terminus / Ubiquitin/SUMO-activating enzyme ubiquitin-like domain / Ubiquitin/SUMO-activating enzyme ubiquitin-like domain / SUMO-activating enzyme subunit Uba2 / Ubiquitin activating enzyme, alpha domain superfamily / Ubiquitin-activating enzyme E1, conserved site / Ubiquitin-activating enzyme signature 1. / Small ubiquitin-related modifier 1, Ubl domain / Ubiquitin/SUMO-activating enzyme E1-like ...SUMO-activating enzyme subunit 2, C-terminal domain / SUMO-activating enzyme subunit 2 C-terminus / Ubiquitin/SUMO-activating enzyme ubiquitin-like domain / Ubiquitin/SUMO-activating enzyme ubiquitin-like domain / SUMO-activating enzyme subunit Uba2 / Ubiquitin activating enzyme, alpha domain superfamily / Ubiquitin-activating enzyme E1, conserved site / Ubiquitin-activating enzyme signature 1. / Small ubiquitin-related modifier 1, Ubl domain / Ubiquitin/SUMO-activating enzyme E1-like / Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 1 / Ubiquitin-activating enzyme E1, Cys active site / Ubiquitin-activating enzyme active site. / ThiF/MoeB/HesA family / THIF-type NAD/FAD binding fold / ThiF family / Ubiquitin-activating enzyme / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-VAY / Small ubiquitin-related modifier 1 / SUMO-activating enzyme subunit 1 / SUMO-activating enzyme subunit 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 Å
AuthorsSintchak, M. / Lane, W. / Bump, N.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.
Authors: Langston, S.P. / Grossman, S. / England, D. / Afroze, R. / Bence, N. / Bowman, D. / Bump, N. / Chau, R. / Chuang, B.C. / Claiborne, C. / Cohen, L. / Connolly, K. / Duffey, M. / Durvasula, N. ...Authors: Langston, S.P. / Grossman, S. / England, D. / Afroze, R. / Bence, N. / Bowman, D. / Bump, N. / Chau, R. / Chuang, B.C. / Claiborne, C. / Cohen, L. / Connolly, K. / Duffey, M. / Durvasula, N. / Freeze, S. / Gallery, M. / Galvin, K. / Gaulin, J. / Gershman, R. / Greenspan, P. / Grieves, J. / Guo, J. / Gulavita, N. / Hailu, S. / He, X. / Hoar, K. / Hu, Y. / Hu, Z. / Ito, M. / Kim, M.S. / Lane, S.W. / Lok, D. / Lublinsky, A. / Mallender, W. / McIntyre, C. / Minissale, J. / Mizutani, H. / Mizutani, M. / Molchinova, N. / Ono, K. / Patil, A. / Qian, M. / Riceberg, J. / Shindi, V. / Sintchak, M.D. / Song, K. / Soucy, T. / Wang, Y. / Xu, H. / Yang, X. / Zawadzka, A. / Zhang, J. / Pulukuri, S.M.
History
DepositionJul 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SUMO-activating enzyme subunit 1
B: SUMO-activating enzyme subunit 2
C: Small ubiquitin-related modifier 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,1656
Polymers121,3893
Non-polymers7763
Water4,576254
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7960 Å2
ΔGint-53 kcal/mol
Surface area36250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.900, 72.422, 126.870
Angle α, β, γ (deg.)90.000, 93.858, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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SUMO-activating enzyme subunit ... , 2 types, 2 molecules AB

#1: Protein SUMO-activating enzyme subunit 1 / Ubiquitin-like 1-activating enzyme E1A


Mass: 38499.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SAE1, AOS1, SUA1, UBLE1A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UBE0
#2: Protein SUMO-activating enzyme subunit 2 / Anthracycline-associated resistance ARX / Ubiquitin-like 1-activating enzyme E1B / Ubiquitin-like ...Anthracycline-associated resistance ARX / Ubiquitin-like 1-activating enzyme E1B / Ubiquitin-like modifier-activating enzyme 2


Mass: 71314.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBA2, SAE2, UBLE1B, HRIHFB2115 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UBT2, Transferases; Acyltransferases; Aminoacyltransferases

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Protein , 1 types, 1 molecules C

#3: Protein Small ubiquitin-related modifier 1 / SUMO-1 / GAP-modifying protein 1 / GMP1 / SMT3 homolog 3 / Sentrin / Ubiquitin-homology domain ...SUMO-1 / GAP-modifying protein 1 / GMP1 / SMT3 homolog 3 / Sentrin / Ubiquitin-homology domain protein PIC1 / Ubiquitin-like protein SMT3C / Smt3C / Ubiquitin-like protein UBL1


Mass: 11575.005 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SUMO1, SMT3C, SMT3H3, UBL1, OK/SW-cl.43 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63165

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Non-polymers , 4 types, 257 molecules

#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-VAY / {(1R,2R,3S,4R)-4-[(5-{4-[(1S)-1-(6-bromopyridin-2-yl)-1-hydroxyethyl]thiophene-2-carbonyl}pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl sulfamate


Mass: 614.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24BrN5O7S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 254 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.19 Å3/Da / Density % sol: 43.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 50 mM BisTris, pH 6.5, 50 mM Ammonium Sulfate, 30% pentaerythritol ethoxylate (Hampton Index 57)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.98→47.702 Å / Num. obs: 71980 / % possible obs: 98.47 % / Redundancy: 3.7 % / Rsym value: 0.093 / Net I/σ(I): 25.7
Reflection shellResolution: 1.98→2.05 Å / Mean I/σ(I) obs: 2.37 / Num. unique obs: 7068 / Rsym value: 0.818 / % possible all: 97.15

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Y8R

1y8r


Resolution: 1.98→47.702 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.239 / WRfactor Rwork: 0.206 / Average fsc free: 0.8974 / Average fsc work: 0.9082 / Cross valid method: FREE R-VALUE / ESU R: 0.173 / ESU R Free: 0.155
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.24 3655 5.078 %
Rwork0.2064 68325 -
all0.208 --
obs-71980 98.465 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 45.146 Å2
Baniso -1Baniso -2Baniso -3
1-0.075 Å20 Å20.632 Å2
2--0.67 Å20 Å2
3----0.822 Å2
Refinement stepCycle: LAST / Resolution: 1.98→47.702 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6634 0 43 254 6931
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0126794
X-RAY DIFFRACTIONr_angle_refined_deg1.6171.6389215
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4625858
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.33723.408314
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.53151120
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7361531
X-RAY DIFFRACTIONr_chiral_restr0.1420.2918
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025080
X-RAY DIFFRACTIONr_nbd_refined0.2280.23096
X-RAY DIFFRACTIONr_nbtor_refined0.3170.24645
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2325
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1590.221
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1740.28
X-RAY DIFFRACTIONr_mcbond_it4.2524.5113477
X-RAY DIFFRACTIONr_mcangle_it5.9036.7144320
X-RAY DIFFRACTIONr_scbond_it5.2744.8143317
X-RAY DIFFRACTIONr_scangle_it7.4587.0734895
X-RAY DIFFRACTIONr_lrange_it9.89261.10610104
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.98-2.0310.2932540.2854927X-RAY DIFFRACTION96.7146
2.031-2.0870.2742410.2584921X-RAY DIFFRACTION98.4175
2.087-2.1470.3132480.254777X-RAY DIFFRACTION98.4908
2.147-2.2130.2892630.2434617X-RAY DIFFRACTION98.7654
2.213-2.2860.2792490.234479X-RAY DIFFRACTION98.8294
2.286-2.3660.2362580.2154328X-RAY DIFFRACTION98.7936
2.366-2.4550.2832150.2234189X-RAY DIFFRACTION99.0108
2.455-2.5550.2452410.2234047X-RAY DIFFRACTION99.0529
2.555-2.6680.2562300.2213893X-RAY DIFFRACTION99.0154
2.668-2.7980.231850.2123726X-RAY DIFFRACTION99.1381
2.798-2.9480.2961860.2153552X-RAY DIFFRACTION99.0986
2.948-3.1270.2831670.2333375X-RAY DIFFRACTION99.1601
3.127-3.3410.2471570.2153181X-RAY DIFFRACTION98.7866
3.341-3.6080.2221520.2062948X-RAY DIFFRACTION98.8205
3.608-3.950.2161440.1882699X-RAY DIFFRACTION98.6126
3.95-4.4120.2091300.162454X-RAY DIFFRACTION97.953
4.412-5.0880.1591220.1522134X-RAY DIFFRACTION97.8742
5.088-6.2130.265850.21860X-RAY DIFFRACTION98.0343
6.213-8.7130.232870.2081413X-RAY DIFFRACTION97.6563
8.713-47.7020.207410.189799X-RAY DIFFRACTION91.3044

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