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- PDB-6xoh: Structure of SUMO1-ML00789344 adduct bound to SAE -

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Basic information

Entry
Database: PDB / ID: 6xoh
TitleStructure of SUMO1-ML00789344 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 complex / SUMO activating enzyme activity / protein localization to nuclear pore / negative regulation of transcription by transcription factor localization / ubiquitin activating enzyme activity / SUMOylation of nuclear envelope proteins / Negative regulation of activity of TFAP2 (AP-2) family transcription factors / SUMO is proteolytically processed / negative regulation of delayed rectifier potassium channel activity / SUMO is conjugated to E1 (UBA2:SAE1) ...SUMO activating enzyme complex / SUMO activating enzyme activity / protein localization to nuclear pore / negative regulation of transcription by transcription factor localization / ubiquitin activating enzyme activity / SUMOylation of nuclear envelope proteins / Negative regulation of activity of TFAP2 (AP-2) family transcription factors / SUMO is proteolytically processed / negative regulation of delayed rectifier potassium channel activity / SUMO is conjugated to E1 (UBA2:SAE1) / PML body organization / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / nuclear stress granule / negative regulation of action potential / positive regulation of protein sumoylation / small protein activating enzyme binding / SUMO binding / regulation of calcium ion transmembrane transport / SUMOylation of DNA methylation proteins / SUMOylation of immune response proteins / XY body / SUMOylation of SUMOylation proteins / ATP-dependent protein binding / Maturation of nucleoprotein / Transferases; Acyltransferases; Aminoacyltransferases / SUMOylation of RNA binding proteins / regulation of cardiac muscle cell contraction / ubiquitin-like protein conjugating enzyme binding / Postmitotic nuclear pore complex (NPC) reformation / Maturation of nucleoprotein / positive regulation of protein targeting to mitochondrion / negative regulation of protein import into nucleus / transcription factor binding / roof of mouth development / SUMOylation of ubiquitinylation proteins / ubiquitin-specific protease binding / negative regulation of DNA binding / ubiquitin-like protein ligase binding / SUMOylation of transcription factors / SUMOylation of DNA replication proteins / protein sumoylation / potassium channel regulator activity / nuclear pore / Regulation of IFNG signaling / SUMOylation of DNA damage response and repair proteins / enzyme activator activity / cellular response to cadmium ion / SUMOylation of chromatin organization proteins / SUMOylation of transcription cofactors / positive regulation of protein-containing complex assembly / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / 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 / cellular response to heat / transferase activity / nuclear membrane / nuclear body / protein stabilization / nuclear speck / protein heterodimerization activity / DNA repair / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / nucleolus / 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 / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Ubiquitin-activating enzyme / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-VB7 / 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: 2.226 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 24, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 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

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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)122,0816
Polymers121,3893
Non-polymers6923
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7850 Å2
ΔGint-53 kcal/mol
Surface area35220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.133, 72.947, 126.586
Angle α, β, γ (deg.)90.000, 92.933, 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, 191 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-VB7 / {(1R,2S,4R)-4-[(5-{4-[(1R)-3,4-dihydro-1H-2-benzopyran-1-yl]thiophene-2-carbonyl}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl sulfamate


Mass: 530.616 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O6S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.21 Å3/Da / Density % sol: 44.3 %
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: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Sep 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.226→47.004 Å / Num. obs: 50291 / % possible obs: 97.02 % / Redundancy: 3.7 % / Rsym value: 0.064 / Net I/σ(I): 18.48
Reflection shellResolution: 2.23→2.31 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 4828 / Rsym value: 0.664

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Y8R

1y8r


Resolution: 2.226→43.31 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.933 / SU B: 6.729 / SU ML: 0.166 / Cross valid method: FREE R-VALUE / ESU R: 0.252 / ESU R Free: 0.209
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2436 2554 5.078 %
Rwork0.1939 47737 -
all0.196 --
obs-50291 96.613 %
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: 63.594 Å2
Baniso -1Baniso -2Baniso -3
1--0.308 Å20 Å22.042 Å2
2--0.534 Å20 Å2
3----0.433 Å2
Refinement stepCycle: LAST / Resolution: 2.226→43.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6479 0 42 188 6709
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0126638
X-RAY DIFFRACTIONr_angle_refined_deg1.4771.6378999
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8915839
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.35623.17306
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.508151097
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4671532
X-RAY DIFFRACTIONr_chiral_restr0.1080.2896
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024955
X-RAY DIFFRACTIONr_nbd_refined0.2250.22993
X-RAY DIFFRACTIONr_nbtor_refined0.3140.24506
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2305
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1940.216
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0840.23
X-RAY DIFFRACTIONr_mcbond_it5.3176.5263401
X-RAY DIFFRACTIONr_mcangle_it7.7139.7254225
X-RAY DIFFRACTIONr_scbond_it6.0916.7393237
X-RAY DIFFRACTIONr_scangle_it8.4989.9744774
X-RAY DIFFRACTIONr_lrange_it11.37587.239819
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.226-2.2840.3291620.28631960.28838180.7810.79387.95180.261
2.284-2.3460.2841980.24733890.24937280.8470.85796.21780.216
2.346-2.4140.2931660.25133160.25336220.8350.85696.13470.216
2.414-2.4880.281710.23432070.23634860.8570.87396.90190.203
2.488-2.5690.281460.21631310.21934140.8740.90195.98710.184
2.569-2.6590.2932020.22229830.22633250.8690.90195.78950.189
2.659-2.7590.2611540.20929320.21231970.9020.91996.5280.187
2.759-2.8720.2711400.20528000.20830270.8890.91997.12590.185
2.872-2.9990.2541410.20827470.2129670.8990.92197.33740.192
2.999-3.1450.3251420.22326100.22928090.8760.90497.97080.216
3.145-3.3140.2391300.19725220.19927020.9150.9398.14950.197
3.314-3.5140.2311420.19623650.19825450.9250.93598.50690.203
3.514-3.7550.2561040.18722500.1923910.9220.9498.45250.201
3.755-4.0540.2021190.17721080.17822550.9450.95198.75830.193
4.054-4.4370.2031270.15519030.15820600.9440.96198.54370.176
4.437-4.9550.195970.14517280.14818550.9540.96498.38270.172
4.955-5.7120.254690.18215720.18516630.9160.94798.67710.213
5.712-6.9690.23600.21313300.21414040.9280.9299.00290.251
6.969-9.750.208540.1710530.17211210.9590.96598.75110.221
9.75-47.0040.3300.2175950.2216520.9020.94195.85890.283

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