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- PDB-6xdf: Crystal structure of IRE1a in complex with G-4100 -

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Basic information

Entry
Database: PDB / ID: 6xdf
TitleCrystal structure of IRE1a in complex with G-4100
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / RNase / Inhibitor / 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 / IRE1-RACK1-PP2A complex / 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 / peptidyl-serine autophosphorylation / IRE1-RACK1-PP2A complex / platelet-derived growth factor receptor binding / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / positive regulation of endoplasmic reticulum unfolded protein response / endothelial cell proliferation / nuclear inner membrane / IRE1-mediated unfolded protein response / mRNA catabolic process / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to vascular endothelial growth factor stimulus / cellular response to unfolded protein / regulation of macroautophagy / positive regulation of JUN kinase activity / 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 / cellular response to glucose stimulus / Hsp90 protein binding / ADP 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. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-N94 / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsSteinbacher, S. / Wang, W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1 alpha Inhibitory Activity.
Authors: Beveridge, R.E. / Wallweber, H.A. / Ashkenazi, A. / Beresini, M. / Clark, K.R. / Gibbons, P. / Ghiro, E. / Kaufman, S. / Larivee, A. / Leblanc, M. / Leclerc, J.P. / Lemire, A. / Ly, C. / ...Authors: Beveridge, R.E. / Wallweber, H.A. / Ashkenazi, A. / Beresini, M. / Clark, K.R. / Gibbons, P. / Ghiro, E. / Kaufman, S. / Larivee, A. / Leblanc, M. / Leclerc, J.P. / Lemire, A. / Ly, C. / Rudolph, J. / Schwarz, J.B. / Srivastava, S. / Wang, W. / Zhao, L. / Braun, M.G.
History
DepositionJun 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)99,1175
Polymers98,6072
Non-polymers5113
Water1,946108
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3100 Å2
ΔGint-14 kcal/mol
Surface area38270 Å2
2
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,7913
Polymers49,3031
Non-polymers4882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3262
Polymers49,3031
Non-polymers231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)166.919, 72.767, 120.054
Angle α, β, γ (deg.)90.000, 129.730, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1159-

HOH

21A-1168-

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: 49303.266 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERN1, IRE1 / 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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-N94 / 4-amino-N-(6-chloro-2-fluoro-3-{[(pyrrolidin-1-yl)sulfonyl]amino}phenyl)quinazoline-8-carboxamide


Mass: 464.901 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18ClFN6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 3.06 Å3/Da / Density % sol: 59.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting 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: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 1, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→92.33 Å / Num. obs: 36523 / % possible obs: 98.8 % / Redundancy: 3.8 % / Biso Wilson estimate: 59.709 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 5.2 / Rrim(I) all: 0.06 / Χ2: 1.037 / Net I/σ(I): 17.69 / Num. measured all: 137624 / Scaling rejects: 86
Reflection shellResolution: 2.54→92.33 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.425 / Mean I/σ(I) obs: 53.08 / Num. unique obs: 154 / CC1/2: 0.996 / Rrim(I) all: 0.029 / % possible all: 98.5

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.54→92.33 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.909 / SU B: 11.558 / SU ML: 0.248 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.44 / ESU R Free: 0.289 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2627 983 2.7 %RANDOM
Rwork0.207 ---
obs0.2086 35540 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 197.41 Å2 / Biso mean: 61.138 Å2 / Biso min: 23.99 Å2
Baniso -1Baniso -2Baniso -3
1-2.7 Å20 Å20.77 Å2
2---2.83 Å20 Å2
3----0.48 Å2
Refinement stepCycle: final / Resolution: 2.54→92.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6499 0 33 108 6640
Biso mean--61.15 51.97 -
Num. residues----802
LS refinement shellResolution: 2.54→2.606 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.436 72 -
Rwork0.37 2562 -
all-2634 -
obs--96.45 %

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