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- PDB-6xdb: Crystal structure of IRE1a in complex with G-6904 -

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Basic information

Entry
Database: PDB / ID: 6xdb
TitleCrystal structure of IRE1a in complex with G-6904
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 / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters ...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 / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / platelet-derived growth factor receptor binding / 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 / regulation of macroautophagy / cellular response to unfolded protein / cellular response to vascular endothelial growth factor stimulus / positive regulation of JUN kinase activity / RNA endonuclease activity / positive regulation of vascular associated smooth muscle cell proliferation / 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-N8S / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsWallweber, H.A. / Weiru, 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 1.1Oct 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)50,3833
Polymers49,5611
Non-polymers8222
Water36020
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.652, 168.441, 101.676
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1108-

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: 49560.508 Da / Num. of mol.: 1
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-N8S / 4-amino-N-(6-chloro-2-fluoro-3-{[(2-fluorophenyl)sulfonyl]amino}phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)quinazoline-8-carboxamide


Mass: 583.997 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H20ClF2N7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


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


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.97 Å3/Da / Density % sol: 58.52 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Hepes pH 7.5, 42% PEG200, 1 M Lithium chloride, 3% w/v 6-Aminohexanoic acid

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.45→43.523 Å / Num. obs: 22097 / % possible obs: 100 % / Redundancy: 6.3 % / Biso Wilson estimate: 64.48 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.026 / Rrim(I) all: 0.065 / Net I/σ(I): 13.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.45-2.586.60.8822084531680.760.3690.9571.5100
7.75-43.525.60.02243807770.9990.010.02443.799.6

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Processing

Software
NameVersionClassification
Aimless0.5.28data scaling
PHENIX1.12-2829_finalrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6URC

6urc


Resolution: 2.45→43.523 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.11 / Phase error: 23.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2274 2000 4.79 %
Rwork0.193 39789 -
obs0.1948 22073 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 172.21 Å2 / Biso mean: 79.0287 Å2 / Biso min: 37.35 Å2
Refinement stepCycle: final / Resolution: 2.45→43.523 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3268 0 55 20 3343
Biso mean--89.89 73.75 -
Num. residues----404
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043407
X-RAY DIFFRACTIONf_angle_d0.6274605
X-RAY DIFFRACTIONf_chiral_restr0.045486
X-RAY DIFFRACTIONf_plane_restr0.004592
X-RAY DIFFRACTIONf_dihedral_angle_d17.3842042
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.4501-2.51140.32171390.28322814
2.5114-2.57930.28071440.27282870
2.5793-2.65520.33221580.2782822
2.6552-2.74080.25841330.25222863
2.7408-2.83880.29171330.24162856
2.8388-2.95240.24581410.23382813
2.9524-3.08680.24891470.23682822
3.0868-3.24950.30311230.24692886
3.2495-3.4530.25221540.23222794
3.453-3.71940.23451340.19662888
3.7194-4.09350.19741580.18542828
4.0935-4.68520.19711350.14812840
4.6852-5.90060.19911370.17472856
5.9006-43.5230.21211640.15732837
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)
10.7354-0.0565-0.42460.7808-0.16970.8330.00220.0844-0.5838-0.17620.1819-0.40090.5508-0.10870.00010.7528-0.0763-0.0260.47230.06690.8783-10.8004-42.886822.1981
22.07560.07710.57561.4746-0.59512.2121-0.1681-0.0812-0.1495-0.10950.0517-0.03080.0746-0.252-00.4015-0.02210.07130.4823-0.00710.4386-19.4093-20.213815.8578
31.26620.46520.32122.1373-0.18091.6756-0.1528-0.06460.30120.3452-0.0483-0.3226-0.4222-0.118300.73990.0495-0.21120.5128-0.05620.5582-12.737410.273622.7674
4-0.0738-0.14420.2740.02960.09830.0962-0.37630.6648-0.0154-0.5983-0.063-0.56340.67570.24090.01360.56870.05120.11750.65160.09780.6758-14.3647-17.74169.095
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and resi 561:644A561 - 644
2X-RAY DIFFRACTION2(chain A and resi 645:832) or (chain L and resi 1)A645 - 832
3X-RAY DIFFRACTION2(chain A and resi 1001)L - A1001
4X-RAY DIFFRACTION3(chain A and resi 833:964)A833 - 964
5X-RAY DIFFRACTION4(chain A and resi 1002)S - A1002

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