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- PDB-4u6r: Crystal structure of human IRE1 cytoplasmic domains in complex wi... -

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Basic information

Entry
Database: PDB / ID: 4u6r
TitleCrystal structure of human IRE1 cytoplasmic domains in complex with a sulfonamide inhibitor.
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / Kinase / Hydrolase / Endoribonuclease / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


peptidyl-serine trans-autophosphorylation / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / Ire1 complex / IRE1alpha activates chaperones / IRE1-TRAF2-ASK1 complex / insulin metabolic process / positive regulation of endoplasmic reticulum unfolded protein response / peptidyl-serine autophosphorylation / platelet-derived growth factor receptor binding ...peptidyl-serine trans-autophosphorylation / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / Ire1 complex / IRE1alpha activates chaperones / IRE1-TRAF2-ASK1 complex / insulin metabolic process / positive regulation of endoplasmic reticulum unfolded protein response / peptidyl-serine autophosphorylation / platelet-derived growth factor receptor binding / IRE1-RACK1-PP2A complex / endothelial cell proliferation / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / nuclear inner membrane / IRE1-mediated unfolded protein response / mRNA catabolic process / positive regulation of JUN kinase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to vascular endothelial growth factor stimulus / regulation of macroautophagy / cellular response to unfolded protein / positive regulation of vascular associated smooth muscle cell proliferation / RNA endonuclease activity / Hsp70 protein binding / response to endoplasmic reticulum stress / positive regulation of RNA splicing / Hsp90 protein binding / cellular response to glucose stimulus / ADP binding / cellular response to hydrogen peroxide / unfolded protein binding / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / endoplasmic reticulum membrane / enzyme binding / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / mitochondrion / ATP binding / identical protein binding / cytoplasm
Similarity search - Function
KEN domain / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / de novo design (two linked rop proteins) ...KEN domain / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / de novo design (two linked rop proteins) / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3E4 / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsMohr, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Unfolded Protein Response in Cancer: IRE1 alpha Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.
Authors: Harrington, P.E. / Biswas, K. / Malwitz, D. / Tasker, A.S. / Mohr, C. / Andrews, K.L. / Dellamaggiore, K. / Kendall, R. / Beckmann, H. / Jaeckel, P. / Materna-Reichelt, S. / Allen, J.R. / Lipford, J.R.
History
DepositionJul 29, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / refine_hist / struct_keywords
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,7709
Polymers52,3751
Non-polymers1,3968
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint-45 kcal/mol
Surface area21070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.847, 86.433, 91.818
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Serine/threonine-protein kinase/endoribonuclease IRE1 / Endoplasmic reticulum-to-nucleus signaling 1 / Inositol-requiring protein 1 / hIRE1p / Ire1-alpha / IRE1a


Mass: 52374.629 Da / Num. of mol.: 1 / Fragment: UNP residues 547-977
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERN1, IRE1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O75460, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 90 molecules

#2: Chemical ChemComp-3E4 / N-{4-[(3-{2-[(trans-4-aminocyclohexyl)amino]pyrimidin-4-yl}pyridin-2-yl)oxy]-3-methylnaphthalen-1-yl}-2-chlorobenzenesulfonamide


Mass: 615.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H31ClN6O3S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsSER TO THR CONFLICT AT THIS POSITION IN UNP ENTRY O75460

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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: 2.91 Å3/Da / Density % sol: 57.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2M Ammonium sulfate, 0.1M HEPES, 25% PEG3350, pH7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Sep 1, 2011
RadiationMonochromator: VariMax HF / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→29.47 Å / Num. obs: 21786 / % possible obs: 98.8 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.089 / Net I/σ(I): 9.7
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.457 / Mean I/σ(I) obs: 4.52 / % possible all: 97.7

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Processing

SoftwareName: REFMAC / Version: 5.8.0049 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P23

3p23


Resolution: 2.5→29.47 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.913 / SU B: 15.495 / SU ML: 0.173 / Cross valid method: THROUGHOUT / ESU R: 0.37 / ESU R Free: 0.258
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24607 1097 5.1 %RANDOM
Rwork0.2017 ---
obs0.20386 20377 98.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.874 Å2
Baniso -1Baniso -2Baniso -3
1-0.69 Å2-0 Å20 Å2
2---0.58 Å2-0 Å2
3----0.11 Å2
Refinement stepCycle: 1 / Resolution: 2.5→29.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3260 0 87 82 3429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0193426
X-RAY DIFFRACTIONr_bond_other_d0.0010.023254
X-RAY DIFFRACTIONr_angle_refined_deg1.351.9824630
X-RAY DIFFRACTIONr_angle_other_deg0.8363.0027457
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0845402
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.41922.963162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.42315594
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8311528
X-RAY DIFFRACTIONr_chiral_restr0.080.2497
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213779
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02806
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3912.891611
X-RAY DIFFRACTIONr_mcbond_other1.3912.8881610
X-RAY DIFFRACTIONr_mcangle_it2.3654.332012
X-RAY DIFFRACTIONr_mcangle_other2.3644.3312013
X-RAY DIFFRACTIONr_scbond_it1.6563.2031815
X-RAY DIFFRACTIONr_scbond_other1.6563.2031815
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.6924.7162619
X-RAY DIFFRACTIONr_long_range_B_refined5.10623.0393774
X-RAY DIFFRACTIONr_long_range_B_other5.07823.0213766
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.502→2.567 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 73 -
Rwork0.244 1471 -
obs--97.6 %
Refinement TLS params.Method: refined / Origin x: 1.461 Å / Origin y: -11.965 Å / Origin z: -20.103 Å
111213212223313233
T0.0043 Å20.0053 Å2-0.0065 Å2-0.0382 Å2-0.0082 Å2--0.0661 Å2
L1.3754 °2-0.3669 °20.6694 °2-1.2458 °2-1.2323 °2--1.7871 °2
S0.038 Å °0.065 Å °0.019 Å °0.0229 Å °-0.0501 Å °0.0852 Å °-0.0121 Å °0.1609 Å °0.0121 Å °

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