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- PDB-3gzn: Structure of NEDD8-activating enzyme in complex with NEDD8 and MLN4924 -

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Basic information

Entry
Database: PDB / ID: 3gzn
TitleStructure of NEDD8-activating enzyme in complex with NEDD8 and MLN4924
Components
  • NEDD8-activating enzyme E1 catalytic subunit
  • NEDD8-activating enzyme E1 regulatory subunit
  • NEDD8
KeywordsPROTEIN BINDING/Ligase / NEDD8 / E1-activating enzyme / MLN4924 / PROTEIN BINDING-Ligase complex
Function / homology
Function and homology information


E1 NEDD8-activating enzyme / NEDD8 activating enzyme activity / endomitotic cell cycle / ubiquitin activating enzyme activity / NEDD8 transferase activity / regulation of proteolysis / mitotic DNA replication checkpoint signaling / protein neddylation / TGF-beta receptor signaling activates SMADs / anatomical structure morphogenesis ...E1 NEDD8-activating enzyme / NEDD8 activating enzyme activity / endomitotic cell cycle / ubiquitin activating enzyme activity / NEDD8 transferase activity / regulation of proteolysis / mitotic DNA replication checkpoint signaling / protein neddylation / TGF-beta receptor signaling activates SMADs / anatomical structure morphogenesis / regulation of neuron apoptotic process / post-translational protein modification / NIK-->noncanonical NF-kB signaling / Dectin-1 mediated noncanonical NF-kB signaling / Iron uptake and transport / protein modification process / modification-dependent protein catabolic process / protein localization / protein tag activity / UCH proteinases / Antigen processing: Ubiquitination & Proteasome degradation / Cargo recognition for clathrin-mediated endocytosis / Neddylation / ubiquitin-dependent protein catabolic process / neuron apoptotic process / regulation of apoptotic process / protein ubiquitination / regulation of cell cycle / protein heterodimerization activity / DNA damage response / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / signal transduction / protein-containing complex / proteolysis / extracellular exosome / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
NEDD8-activating enzyme E1, catalytic subunit / NEDD8-activating enzyme E1 regulatory subunit APP-BP1 / E2 binding / NEDD8-activating enzyme E1 catalytic subunit / E2 binding domain / E2_bind / Ubiquitin activating enzymes (Uba3). Chain: B, domain 2 / Ubiquitin activating enzyme, alpha domain superfamily / Nedd8-like ubiquitin / Ubiquitin-activating enzyme E1, Cys active site ...NEDD8-activating enzyme E1, catalytic subunit / NEDD8-activating enzyme E1 regulatory subunit APP-BP1 / E2 binding / NEDD8-activating enzyme E1 catalytic subunit / E2 binding domain / E2_bind / Ubiquitin activating enzymes (Uba3). Chain: B, domain 2 / Ubiquitin activating enzyme, alpha domain superfamily / Nedd8-like ubiquitin / Ubiquitin-activating enzyme E1, Cys active site / Ubiquitin-activating enzyme active site. / ThiF/MoeB/HesA family / Ubiquitin-activating enzyme / THIF-type NAD/FAD binding fold / ThiF family / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin domain signature. / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Arc Repressor Mutant, subunit A / Ubiquitin-like domain superfamily / NAD(P)-binding Rossmann-like Domain / Roll / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-B39 / NEDD8-activating enzyme E1 regulatory subunit / NEDD8 / NEDD8-activating enzyme E1 catalytic subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsSintchak, M.D.
CitationJournal: Mol.Cell / Year: 2010
Title: Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.
Authors: Brownell, J.E. / Sintchak, M.D. / Gavin, J.M. / Liao, H. / Bruzzese, F.J. / Bump, N.J. / Soucy, T.A. / Milhollen, M.A. / Yang, X. / Burkhardt, A.L. / Ma, J. / Loke, H.K. / Lingaraj, T. / Wu, ...Authors: Brownell, J.E. / Sintchak, M.D. / Gavin, J.M. / Liao, H. / Bruzzese, F.J. / Bump, N.J. / Soucy, T.A. / Milhollen, M.A. / Yang, X. / Burkhardt, A.L. / Ma, J. / Loke, H.K. / Lingaraj, T. / Wu, D. / Hamman, K.B. / Spelman, J.J. / Cullis, C.A. / Langston, S.P. / Vyskocil, S. / Sells, T.B. / Mallender, W.D. / Visiers, I. / Li, P. / Claiborne, C.F. / Rolfe, M. / Bolen, J.B. / Dick, L.R.
History
DepositionApr 7, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 21, 2012Group: Database references
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NEDD8-activating enzyme E1 regulatory subunit
B: NEDD8-activating enzyme E1 catalytic subunit
C: NEDD8-activating enzyme E1 regulatory subunit
D: NEDD8-activating enzyme E1 catalytic subunit
I: NEDD8
J: NEDD8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)244,26610
Polymers243,2486
Non-polymers1,0184
Water0
1
A: NEDD8-activating enzyme E1 regulatory subunit
B: NEDD8-activating enzyme E1 catalytic subunit
I: NEDD8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,1335
Polymers121,6243
Non-polymers5092
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10080 Å2
ΔGint-36 kcal/mol
Surface area41380 Å2
MethodPISA
2
C: NEDD8-activating enzyme E1 regulatory subunit
D: NEDD8-activating enzyme E1 catalytic subunit
J: NEDD8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,1335
Polymers121,6243
Non-polymers5092
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10090 Å2
ΔGint-35 kcal/mol
Surface area41220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.030, 228.715, 229.307
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein NEDD8-activating enzyme E1 regulatory subunit / Amyloid protein-binding protein 1 / Amyloid beta precursor protein-binding protein 1 / 59 kDa / APP- ...Amyloid protein-binding protein 1 / Amyloid beta precursor protein-binding protein 1 / 59 kDa / APP-BP1 / Proto-oncogene protein 1


Mass: 60315.102 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APPBP1, HPP1, NAE1 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9 / References: UniProt: Q13564
#2: Protein NEDD8-activating enzyme E1 catalytic subunit / Ubiquitin-like modifier-activating enzyme 3 / Ubiquitin-activating enzyme 3 / NEDD8-activating ...Ubiquitin-like modifier-activating enzyme 3 / Ubiquitin-activating enzyme 3 / NEDD8-activating enzyme E1C / Ubiquitin-activating enzyme E1C


Mass: 51906.180 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBA3, UBE1C / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: Q8TBC4, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#3: Protein NEDD8 / / Ubiquitin-like protein Nedd8 / Neddylin / Neural precursor cell expressed developmentally down- ...Ubiquitin-like protein Nedd8 / Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8


Mass: 9402.857 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NEDD8 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9 / References: UniProt: Q15843
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-B39 / [(1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl]methyl sulfamate


Mass: 443.519 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25N5O4S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.62 Å3/Da / Density % sol: 66.06 %
Crystal growTemperature: 293 K
Details: 1.8 M tri-ammonium citrate pH 7.0, 4% (v/v) 1,3 butanediol, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 16, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 3→49.36 Å / % possible obs: 92.3 % / Redundancy: 5.9 % / Rmerge(I) obs: 0.094 / Net I/σ(I): 15.9

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Processing

SoftwareName: REFMAC / Version: 5.2.0005 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R4M

1r4m


Resolution: 3→49.36 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.887 / SU B: 18.24 / SU ML: 0.336 / Cross valid method: THROUGHOUT / ESU R: 2.059 / ESU R Free: 0.435 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28702 3515 5 %RANDOM
Rwork0.23046 ---
obs0.23325 66102 97.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 66.768 Å2
Baniso -1Baniso -2Baniso -3
1-6.91 Å20 Å20 Å2
2---3.48 Å20 Å2
3----3.43 Å2
Refinement stepCycle: LAST / Resolution: 3→49.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15986 0 64 0 16050
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.02216389
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1471.96422294
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.66252060
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.56824.772746
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.111152663
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8841585
X-RAY DIFFRACTIONr_chiral_restr0.080.22540
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02112493
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2110.27573
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3080.211181
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2466
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1780.238
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1260.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.577210315
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.086316612
X-RAY DIFFRACTIONr_scbond_it0.87136074
X-RAY DIFFRACTIONr_scangle_it1.44545682
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3→3.079 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 262 -
Rwork0.308 4811 -
obs--96.81 %

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