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- PDB-6w3k: Structure of unphosphorylated human IRE1 bound to G-9807 -

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Basic information

Entry
Database: PDB / ID: 6w3k
TitleStructure of unphosphorylated human IRE1 bound to G-9807
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / allosteric activator / UPR / TRANSFERASE / 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 / peptidyl-serine autophosphorylation / positive regulation of endoplasmic reticulum unfolded protein response / IRE1-RACK1-PP2A complex ...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 / peptidyl-serine autophosphorylation / positive regulation of endoplasmic reticulum unfolded protein response / IRE1-RACK1-PP2A complex / platelet-derived growth factor receptor binding / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / nuclear inner membrane / endothelial cell proliferation / IRE1-mediated unfolded protein response / mRNA catabolic process / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to unfolded protein / cellular response to vascular endothelial growth factor stimulus / regulation of macroautophagy / positive regulation of JUN kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / response to endoplasmic reticulum stress / Hsp70 protein binding / RNA endonuclease activity / positive regulation of RNA splicing / cellular response to glucose stimulus / ADP binding / Hsp90 protein binding / cellular response to hydrogen peroxide / unfolded protein binding / protein autophosphorylation / 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
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 / Quinoprotein alcohol dehydrogenase-like superfamily / Serine/threonine-protein kinase, active site ...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 / Quinoprotein alcohol dehydrogenase-like superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / WD40/YVTN repeat-like-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-SJS / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsLammens, A. / Wang, W. / Ferri, E. / Rudolph, J.
CitationJournal: Nat Commun / Year: 2020
Title: Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.
Authors: Ferri, E. / Le Thomas, A. / Wallweber, H.A. / Day, E.S. / Walters, B.T. / Kaufman, S.E. / Braun, M.G. / Clark, K.R. / Beresini, M.H. / Mortara, K. / Chen, Y.A. / Canter, B. / Phung, W. / ...Authors: Ferri, E. / Le Thomas, A. / Wallweber, H.A. / Day, E.S. / Walters, B.T. / Kaufman, S.E. / Braun, M.G. / Clark, K.R. / Beresini, M.H. / Mortara, K. / Chen, Y.A. / Canter, B. / Phung, W. / Liu, P.S. / Lammens, A. / Ashkenazi, A. / Rudolph, J. / Wang, W.
History
DepositionMar 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jun 16, 2021Group: Derived calculations / Category: pdbx_struct_oper_list
Item: _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation ..._pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.vector[1] / _pdbx_struct_oper_list.vector[3]
Revision 1.3Oct 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: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,9862
Polymers49,5611
Non-polymers4241
Water2,306128
1
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)99,9724
Polymers99,1232
Non-polymers8492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_454-x-1,y,-z-11
Unit cell
Length a, b, c (Å)73.513, 112.761, 67.892
Angle α, β, γ (deg.)90.000, 119.580, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1181-

HOH

21A-1217-

HOH

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Components

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


Mass: 49561.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERN1, IRE1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O75460, non-specific serine/threonine protein kinase, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
#2: Chemical ChemComp-SJS / 4-[5-[2,6-bis(fluoranyl)phenyl]-2~{H}-pyrazolo[3,4-b]pyridin-3-yl]-2-(4-oxidanylpiperidin-1-yl)-1~{H}-pyrimidin-6-one


Mass: 424.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18F2N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
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: 2.47 Å3/Da / Density % sol: 50.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 10% (v/v) isopropanol, 11% (w/v) PEG4000, 0.1 M Na-citrate, pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.932→55.614 Å / Num. obs: 27588 / % possible obs: 86.6 % / Redundancy: 2.9 % / Biso Wilson estimate: 40.86 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.04 / Rrim(I) all: 0.071 / Net I/σ(I): 10.2 / Num. measured all: 80019
Reflection shell

Num. unique obs: 1379 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.932-2.0952.80.71938540.6070.50.881.233.8
5.673-55.6142.90.04140510.9950.0290.05125.194.8

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.12-2829_finalrefinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5HGI

5hgi


Resolution: 2.08→55.614 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 24.03
RfactorNum. reflection% reflection
Rfree0.2174 1257 4.74 %
Rwork0.1905 --
obs0.1918 26537 91.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 187.2 Å2 / Biso mean: 61.4903 Å2 / Biso min: 22.23 Å2
Refinement stepCycle: final / Resolution: 2.08→55.614 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3224 0 31 128 3383
Biso mean--48.66 54.38 -
Num. residues----398
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.57660.2724-0.71080.8766-0.83641.69910.2296-0.01110.97180.22880.11850.0461-0.924-0.14120.00070.72360.04570.07030.40630.01190.7311-22.72628.772-18.382
22.6649-0.5221-1.24271.9009-0.32653.34-0.0688-0.40510.0530.11160.0038-0.11240.03970.1584-0.00140.2511-0.0134-0.04120.3465-0.00930.2651-21.2536.296-8.366
31.8195-0.7085-1.54312.40381.13114.8955-0.5195-0.1443-1.03950.2836-0.3499-0.19611.39220.0106-0.08330.7549-0.050.25420.35490.08110.8456-23.605-24.032-17.012
40.9882-0.2868-0.48080.623-0.06591.0361-0.0187-0.0788-0.0678-0.0242-0.0220.0755-0.0519-0.02070.00010.3919-0.0038-0.01720.4708-0.02760.3456-24.3793.237-14.092
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 562:644 )A562 - 644
2X-RAY DIFFRACTION2( CHAIN A AND ( RESID 645:832 OR RESID 1001:1001 ) )A645 - 832
3X-RAY DIFFRACTION2( CHAIN A AND ( RESID 645:832 OR RESID 1001:1001 ) )A1001
4X-RAY DIFFRACTION3( CHAIN A AND RESID 833:963 )A833 - 963
5X-RAY DIFFRACTION4( CHAIN A AND RESID 1101:1228 )A1101 - 1228

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