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- PDB-5ebz: Crystal structure of human IKK1 -

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Basic information

Entry
Database: PDB / ID: 5ebz
TitleCrystal structure of human IKK1
ComponentsInhibitor of nuclear factor kappa-B kinase subunit alpha
KeywordsTransferase/transferase inhibitor / kinase / inhibitor / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


response to acetate / IkappaB kinase / IkappaB kinase activity / IKBKB deficiency causes SCID / IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) / response to cholecystokinin / IkappaB kinase complex / SLC15A4:TASL-dependent IRF5 activation / I-kappaB phosphorylation / transferrin receptor binding ...response to acetate / IkappaB kinase / IkappaB kinase activity / IKBKB deficiency causes SCID / IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) / response to cholecystokinin / IkappaB kinase complex / SLC15A4:TASL-dependent IRF5 activation / I-kappaB phosphorylation / transferrin receptor binding / IkBA variant leads to EDA-ID / CD40 receptor complex / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / RIP-mediated NFkB activation via ZBP1 / AKT phosphorylates targets in the cytosol / non-canonical NF-kappaB signal transduction / response to hydroperoxide / toll-like receptor 4 signaling pathway / negative regulation of NF-kappaB transcription factor activity / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of interferon-alpha production / TRAF6 mediated NF-kB activation / Rho protein signal transduction / skeletal muscle contraction / anatomical structure morphogenesis / response to amino acid / canonical NF-kappaB signal transduction / tumor necrosis factor-mediated signaling pathway / striated muscle cell differentiation / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / cellular response to cadmium ion / TICAM1, RIP1-mediated IKK complex recruitment / MAP3K8 (TPL2)-dependent MAPK1/3 activation / IKK complex recruitment mediated by RIP1 / TNFR1-induced NF-kappa-B signaling pathway / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Dectin-1 mediated noncanonical NF-kB signaling / Regulation of TNFR1 signaling / Activation of NF-kappaB in B cells / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / response to virus / PKR-mediated signaling / cellular response to virus / CLEC7A (Dectin-1) signaling / response to toxic substance / FCERI mediated NF-kB activation / cytoplasmic side of plasma membrane / Interleukin-1 signaling / cellular response to reactive oxygen species / Downstream TCR signaling / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / scaffold protein binding / positive regulation of canonical NF-kappaB signal transduction / response to lipopolysaccharide / protein kinase activity / inflammatory response / immune response / response to xenobiotic stimulus / protein heterodimerization activity / protein phosphorylation / innate immune response / protein serine/threonine kinase activity / protein-containing complex binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / cytosol / cytoplasm
Similarity search - Function
I-kappa-kinase-beta NEMO binding domain / IKBKB, scaffold dimerization domain / IKBKB, scaffold dimerization domain superfamily / I-kappa-kinase-beta NEMO binding domain / IQBAL scaffold dimerization domain / I-kappa-kinase-beta NEMO binding domain / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...I-kappa-kinase-beta NEMO binding domain / IKBKB, scaffold dimerization domain / IKBKB, scaffold dimerization domain superfamily / I-kappa-kinase-beta NEMO binding domain / IQBAL scaffold dimerization domain / I-kappa-kinase-beta NEMO binding domain / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
2-azanyl-5-phenyl-3-(4-sulfamoylphenyl)benzamide / Inhibitor of nuclear factor kappa-B kinase subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 4.5 Å
AuthorsPolley, S. / Passos, D. / Huang, D. / Biswas, T. / Verma, I. / Lyumkis, D. / Ghosh, G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA141722 United States
CitationJournal: Cell Rep / Year: 2016
Title: Structural Basis for the Activation of IKK1/α.
Authors: Smarajit Polley / Dario Oliveira Passos / De-Bin Huang / Maria Carmen Mulero / Anup Mazumder / Tapan Biswas / Inder M Verma / Dmitry Lyumkis / Gourisankar Ghosh /
Abstract: Distinct signaling pathways activate the NF-κB family of transcription factors. The canonical NF-κB-signaling pathway is mediated by IκB kinase 2/β (IKK2/β), while the non-canonical pathway ...Distinct signaling pathways activate the NF-κB family of transcription factors. The canonical NF-κB-signaling pathway is mediated by IκB kinase 2/β (IKK2/β), while the non-canonical pathway depends on IKK1/α. The structural and biochemical bases for distinct signaling by these otherwise highly similar IKKs are unclear. We report single-particle cryoelectron microscopy (cryo-EM) and X-ray crystal structures of human IKK1 in dimeric (∼150 kDa) and hexameric (∼450 kDa) forms. The hexamer, which is the representative form in the crystal but comprises only ∼2% of the particles in solution by cryo-EM, is a trimer of IKK1 dimers. While IKK1 hexamers are not detectable in cells, the surface that supports hexamer formation is critical for IKK1-dependent cellular processing of p100 to p52, the hallmark of non-canonical NF-κB signaling. Comparison of this surface to that in IKK2 indicates significant divergence, and it suggests a fundamental role for this surface in signaling by these kinases through distinct pathways.
History
DepositionOct 20, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Sep 6, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Data collection / Category: chem_comp / pdbx_audit_support
Item: _chem_comp.type / _pdbx_audit_support.funding_organization
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _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.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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Mar 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Inhibitor of nuclear factor kappa-B kinase subunit alpha
B: Inhibitor of nuclear factor kappa-B kinase subunit alpha
C: Inhibitor of nuclear factor kappa-B kinase subunit alpha
D: Inhibitor of nuclear factor kappa-B kinase subunit alpha
E: Inhibitor of nuclear factor kappa-B kinase subunit alpha
F: Inhibitor of nuclear factor kappa-B kinase subunit alpha
G: Inhibitor of nuclear factor kappa-B kinase subunit alpha
H: Inhibitor of nuclear factor kappa-B kinase subunit alpha
I: Inhibitor of nuclear factor kappa-B kinase subunit alpha
J: Inhibitor of nuclear factor kappa-B kinase subunit alpha
K: Inhibitor of nuclear factor kappa-B kinase subunit alpha
L: Inhibitor of nuclear factor kappa-B kinase subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)933,78052
Polymers901,76312
Non-polymers32,01740
Water00
1
A: Inhibitor of nuclear factor kappa-B kinase subunit alpha
B: Inhibitor of nuclear factor kappa-B kinase subunit alpha
C: Inhibitor of nuclear factor kappa-B kinase subunit alpha
D: Inhibitor of nuclear factor kappa-B kinase subunit alpha
E: Inhibitor of nuclear factor kappa-B kinase subunit alpha
F: Inhibitor of nuclear factor kappa-B kinase subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)466,89026
Polymers450,8826
Non-polymers16,00820
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area32070 Å2
ΔGint-2 kcal/mol
Surface area181470 Å2
MethodPISA
2
G: Inhibitor of nuclear factor kappa-B kinase subunit alpha
H: Inhibitor of nuclear factor kappa-B kinase subunit alpha
I: Inhibitor of nuclear factor kappa-B kinase subunit alpha
J: Inhibitor of nuclear factor kappa-B kinase subunit alpha
K: Inhibitor of nuclear factor kappa-B kinase subunit alpha
L: Inhibitor of nuclear factor kappa-B kinase subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)466,89026
Polymers450,8826
Non-polymers16,00820
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area31390 Å2
ΔGint7 kcal/mol
Surface area180120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)174.510, 186.940, 275.830
Angle α, β, γ (deg.)90.00, 98.84, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Inhibitor of nuclear factor kappa-B kinase subunit alpha / IkappaB kinase / Conserved helix-loop-helix ubiquitous kinase / I-kappa-B kinase 1 / IKK1 / Nuclear ...IkappaB kinase / Conserved helix-loop-helix ubiquitous kinase / I-kappa-B kinase 1 / IKK1 / Nuclear factor NF-kappa-B inhibitor kinase alpha / NFKBIKA / Transcription factor 16 / TCF-16


Mass: 75146.945 Da / Num. of mol.: 12 / Mutation: S176E, S180E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHUK, IKKA, TCF16 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O15111, IkappaB kinase
#2: Polysaccharide...
2,3-di-O-sulfo-alpha-D-glucopyranose-(1-6)-alpha-D-glucopyranose-(1-6)-2,4-di-O-sulfo-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 824.690 Da / Num. of mol.: 24 / Source method: obtained synthetically
DescriptorTypeProgram
WURCS=2.0/3,3,2/[a2122h-1a_1-5_2*OSO/3=O/3=O_4*OSO/3=O/3=O][a2122h-1a_1-5][a2122h-1a_1-5_2*OSO/3=O/3=O_3*OSO/3=O/3=O]/1-2-3/a6-b1_b6-c1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp2SO34SO3]{[(6+1)][a-D-Glcp]{[(6+1)][a-D-Glcp2SO33SO3]{}}}LINUCSPDB-CARE
#3: Polysaccharide
[(2S,3R,4S,5S,6R)-6-(hydroxymethyl)-2,4-bis(oxidanyl)-5-oxidanylsulfanyloxy-oxan-3-yl] hydrogen ...[(2S,3R,4S,5S,6R)-6-(hydroxymethyl)-2,4-bis(oxidanyl)-5-oxidanylsulfanyloxy-oxan-3-yl] hydrogen sulfate-(1-6)-(2S,3R,4R,5S,6R)-6-(hydroxymethyl)-5-oxidanylsulfanyloxy-oxane-2,3,4-triol-(1-6)-2-O-sulfo-alpha-D-glucopyranose-(1-6)-[(2R,3R,4R,5R,6S)-2-(hydroxymethyl)-5,6-bis(oxidanyl)-3-oxidanylsulfanyloxy-oxan-4-yl] hydrogen sulfate-(1-6)-[(2S,3R,4S,5R,6R)-6-(hydroxymethyl)-2,5-bis(oxidanyl)-4-oxidanylsulfanyloxy-oxan-3-yl] hydrogen sulfate-(1-6)-[(2R,3R,4R,5R,6S)-2-(hydroxymethyl)-5,6-bis(oxidanyl)-3-oxidanylsulfanyloxy-oxan-4-yl] hydrogen sulfate-(1-6)-2,4-di-O-sulfo-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 1953.762 Da / Num. of mol.: 4 / Source method: obtained synthetically
DescriptorTypeProgram
WURCS=2.0/6,7,6/[a2122h-1a_1-5_2*OSO/3=O/3=O_4*OSO/3=O/3=O][a2122h-1a_1-5_3*OSO/3=O/3=O_4*OSO][a2122h-1a_1-5_2*OSO/3=O/3=O_3*OSO][a2122h-1a_1-5_2*OSO/3=O/3=O][a2122h-1a_1-5_4*OSO][a2122h-1a_1-5_2*OSO/3=O/3=O_4*OSO]/1-2-3-2-4-5-6/a6-b1_b6-c1_c6-d1_d6-e1_e6-f1_f6-g1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp2SO34SO3]{[(6+1)][a-D-Glcp3SO3]{[(6+1)][a-D-Glcp2SO3]{[(6+1)][a-D-Glcp3SO3]{[(6+1)][a-D-Glcp2SO3]{[(6+1)][a-D-Glcp]{[(6+1)][a-D-Glcp2SO3]{}}}}}}}LINUCSPDB-CARE
#4: Chemical
ChemComp-5TL / 2-azanyl-5-phenyl-3-(4-sulfamoylphenyl)benzamide


Mass: 367.422 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C19H17N3O3S

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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: 4.93 Å3/Da / Density % sol: 75.05 %
Crystal growTemperature: 277 K / Method: evaporation / Details: PEG, Dextran Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97927 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97927 Å / Relative weight: 1
ReflectionResolution: 4.5→45 Å / Num. obs: 99808 / % possible obs: 95.5 % / Observed criterion σ(F): 1 / Redundancy: 7 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 5.2
Reflection shellResolution: 4.5→4.58 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.81 / Mean I/σ(I) obs: 1.5 / % possible all: 88

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Processing

Software
NameVersionClassification
CNS1.3refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
MOLREPphasing
RefinementResolution: 4.5→29.94 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 95567.81 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 1 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.276 2851 4 %RANDOM
Rwork0.238 ---
obs0.238 70648 68.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 236.747 Å2 / ksol: 0.28 e/Å3
Displacement parametersBiso mean: 267.7 Å2
Baniso -1Baniso -2Baniso -3
1-78.8 Å20 Å2-3.73 Å2
2---55.52 Å20 Å2
3----23.28 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.91 Å0.82 Å
Luzzati d res low-5 Å
Luzzati sigma a0.62 Å1.39 Å
Refinement stepCycle: LAST / Resolution: 4.5→29.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms63156 0 1976 0 65132
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.39
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 4.5→4.78 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.474 381 4.6 %
Rwork0.462 7985 -
obs--48.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1CNS_TOPPAR/protein_rep.paramCNS_TOPPAR/protein.top
X-RAY DIFFRACTION2CNS_TOPPAR/dna-rna_rep.paramCNS_TOPPAR/dna-rna.top
X-RAY DIFFRACTION3CNS_TOPPAR/water_rep.paramCNS_TOPPAR/water.top
X-RAY DIFFRACTION4CNS_TOPPAR/ion.paramCNS_TOPPAR/ion.top
X-RAY DIFFRACTION5gls3.paramgls3d.top
X-RAY DIFFRACTION6CNS_TOPPAR/xnn7.paramxnn.top
X-RAY DIFFRACTION7XNM.parinh.top

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