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- PDB-6xdd: Crystal structure of IRE1 in complex with G-3053 -

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Basic information

Entry
Database: PDB / ID: 6xdd
TitleCrystal structure of IRE1 in complex with G-3053
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE/INHIBITOR / KInase / RNase / inhibitor / 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-N97 / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsAckerly-Wallweber, H. / 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 1.1Oct 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

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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)100,8254
Polymers99,6032
Non-polymers1,2222
Water55831
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2710 Å2
ΔGint11 kcal/mol
Surface area38310 Å2
2
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,4122
Polymers49,8011
Non-polymers6111
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)50,4122
Polymers49,8011
Non-polymers6111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.201, 156.816, 157.766
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 49801.430 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-N97 / 4-[(trans-4-aminocyclohexyl)amino]-N-(6-chloro-3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)thieno[3,2-d]pyrimidine-7-carboxamide


Mass: 611.059 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H22ClF3N6O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.93 Å3/Da / Density % sol: 58.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 10% 2-propanol, 0.1 M sodium citrate tribasic dihydrate pH 5.0, and 26% PEG400, 4% pentaerythritol ethoxylate (3/4 EO/OH), 4% 1,3-Propanediol

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→49.62 Å / Num. obs: 45858 / % possible obs: 97.7 % / Redundancy: 6.6 % / Biso Wilson estimate: 55.21 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.024 / Rrim(I) all: 0.061 / Net I/σ(I): 19.2
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
2.4-2.5370.6754685667380.9090.2750.732.4100
7.59-49.625.80.022961316630.9990.010.02459.599.5

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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: 2.4→49.619 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.26 / Phase error: 25.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2381 4057 4.71 %
Rwork0.1984 82054 -
obs0.2002 45769 97.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 142.87 Å2 / Biso mean: 63.8392 Å2 / Biso min: 34.28 Å2
Refinement stepCycle: final / Resolution: 2.4→49.619 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6560 0 80 31 6671
Biso mean--62.8 52.14 -
Num. residues----808
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0056808
X-RAY DIFFRACTIONf_angle_d0.7739210
X-RAY DIFFRACTIONf_chiral_restr0.048976
X-RAY DIFFRACTIONf_plane_restr0.0051182
X-RAY DIFFRACTIONf_dihedral_angle_d16.3394074
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4-2.42830.30921210.28432886100
2.4283-2.45790.27831180.27292989100
2.4579-2.4890.30181740.26072919100
2.489-2.52180.26211260.25312840100
2.5218-2.55630.2991670.26152920100
2.5563-2.59280.27721120.2552921100
2.5928-2.63150.3031600.2592893100
2.6315-2.67260.33861420.2517234696
2.6726-2.71640.27021270.2551237496
2.7164-2.76330.33731770.26332900100
2.7633-2.81350.2661560.2387286799
2.8135-2.86760.29411580.2353285199
2.8676-2.92620.31781090.2445293899
2.9262-2.98980.32691640.23572851100
2.9898-3.05930.32341370.24912914100
3.0593-3.13580.2261170.2282957100
3.1358-3.22060.29591330.23552878100
3.2206-3.31530.26871910.25212854100
3.3153-3.42230.3261810.22872889100
3.4223-3.54460.28681240.2135242085
3.5446-3.68650.23551370.2029292299
3.6865-3.85420.24711480.1901286099
3.8542-4.05730.199870.1787243983
4.0573-4.31140.1961480.16222929100
4.3114-4.6440.20971380.14632886100
4.644-5.1110.1941290.15392894100
5.111-5.84950.17151090.1776293299
5.8495-7.36590.15611120.18662901100
7.3659-49.6190.19751550.1659288499
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)
11.7402-0.27830.21561.315-0.89991.2484-0.1616-0.8175-0.06610.54570.12520.0378-0.1772-0.0444-00.60860.0196-0.01670.82790.16370.6396-3.9371-22.783677.3352
21.58740.15150.72383.90170.27452.8264-0.028-0.296-0.00690.3111-0.0572-0.0287-0.58330.034900.5421-0.0449-0.05350.58410.06690.5133-6.2977-0.320568.0839
33.14580.5638-0.00262.34570.14142.58680.1453-0.06680.08420.0396-0.13150.0577-0.1204-0.20420.00010.6226-0.0179-0.02540.44820.03040.4771-4.492215.161639.1107
41.58320.46020.16371.8656-0.66142.2472-0.1987-0.2446-0.6558-0.28990.136-0.2430.70340.1767-0.00030.5668-0.00670.03820.67070.13050.6815-11.782-38.715562.4116
52.0842-0.6107-0.04823.60170.12633.43070.05730.021-0.1561-0.51170.0090.09920.0851-0.12440.00010.4104-0.0993-0.01750.43540.04040.4979-11.0304-30.684438.5466
62.8562-0.20130.14292.9911-0.1261.83810.14740.14140.0534-0.2364-0.0946-0.113-0.00010.02880.00010.60850.0032-0.00660.4650.04550.4707-13.7758-2.499922.626
70.4070.3911-0.04940.3402-0.01890.07060.0234-0.14860.00790.032-0.04280.1236-0.0286-0.2021-0.00020.3736-0.00280.00180.40930.10360.3744-6.4788-14.155551.6417
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and resi 560:644A560 - 963
2X-RAY DIFFRACTION2(chain A and resi 645:832) or (chain L and resi 1)A560 - 963
3X-RAY DIFFRACTION2(chain A and resi 645:832) or (chain L and resi 1)L0
4X-RAY DIFFRACTION3(chain A and resi 833:970)A560 - 963
5X-RAY DIFFRACTION4chain B and resi 560:644B560 - 963
6X-RAY DIFFRACTION5(chain B and resi 645:832) or (chain L and resi 2)B560 - 963
7X-RAY DIFFRACTION5(chain B and resi 645:832) or (chain L and resi 2)L0
8X-RAY DIFFRACTION6(chain B and resi 833:970)B560 - 963
9X-RAY DIFFRACTION7(chain S or (chain L and resi 3:9))S0

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