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- PDB-6urc: Crystal structure of IRE1a in complex with compound 18 -

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Basic information

Entry
Database: PDB / ID: 6urc
TitleCrystal structure of IRE1a in complex with compound 18
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
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 / de novo design (two linked rop proteins) / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat ...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 / de novo design (two linked rop proteins) / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / Quinoprotein alcohol dehydrogenase-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QFV / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsWallweber, H.H. / Wang, W.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2019
Title: Disruption of IRE1 alpha through its kinase domain attenuates multiple myeloma.
Authors: Harnoss, J.M. / Le Thomas, A. / Shemorry, A. / Marsters, S.A. / Lawrence, D.A. / Lu, M. / Chen, Y.A. / Qing, J. / Totpal, K. / Kan, D. / Segal, E. / Merchant, M. / Reichelt, M. / Ackerly ...Authors: Harnoss, J.M. / Le Thomas, A. / Shemorry, A. / Marsters, S.A. / Lawrence, D.A. / Lu, M. / Chen, Y.A. / Qing, J. / Totpal, K. / Kan, D. / Segal, E. / Merchant, M. / Reichelt, M. / Ackerly Wallweber, H. / Wang, W. / Clark, K. / Kaufman, S. / Beresini, M.H. / Laing, S.T. / Sandoval, W. / Lorenzo, M. / Wu, J. / Ly, J. / De Bruyn, T. / Heidersbach, A. / Haley, B. / Gogineni, A. / Weimer, R.M. / Lee, D. / Braun, M.G. / Rudolph, J. / VanWyngarden, M.J. / Sherbenou, D.W. / Gomez-Bougie, P. / Amiot, M. / Acosta-Alvear, D. / Walter, P. / Ashkenazi, A.
History
DepositionOct 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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
B: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,4175
Polymers99,1232
Non-polymers1,2943
Water10,611589
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3140 Å2
ΔGint10 kcal/mol
Surface area37890 Å2
2
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,2553
Polymers49,5611
Non-polymers6932
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)50,1632
Polymers49,5611
Non-polymers6011
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.120, 84.660, 175.510
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: 49561.496 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-QFV / 2-chloro-N-(6-methyl-5-{[3-(2-{[(3S)-piperidin-3-yl]amino}pyrimidin-4-yl)pyridin-2-yl]oxy}naphthalen-1-yl)benzene-1-sulfonamide


Mass: 601.118 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H29ClN6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 589 / 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: 2.52 Å3/Da / Density % sol: 51.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M trisodium citrate pH 5.6, 10% isopropanol, 10% PEG4000, and cesium chloride

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 97741 / % possible obs: 100 % / Redundancy: 7.1 % / Biso Wilson estimate: 18.59 Å2 / CC1/2: 0.996 / Net I/σ(I): 7.6
Reflection shellResolution: 2.2→2.207 Å / Num. unique obs: 495 / CC1/2: 0.903

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P23

3p23


Resolution: 2.2→44.102 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.07 / Phase error: 32
RfactorNum. reflection% reflection
Rfree0.274 4989 5.1 %
Rwork0.2202 --
obs0.223 97741 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 111.25 Å2 / Biso mean: 26.4432 Å2 / Biso min: 2.9 Å2
Refinement stepCycle: final / Resolution: 2.2→44.102 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6437 0 90 589 7116
Biso mean--16.66 29.88 -
Num. residues----798
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0066692
X-RAY DIFFRACTIONf_angle_d0.9259040
X-RAY DIFFRACTIONf_chiral_restr0.036962
X-RAY DIFFRACTIONf_plane_restr0.0041164
X-RAY DIFFRACTIONf_dihedral_angle_d13.5122495
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.2-2.2250.33231770.28423110100
2.225-2.25120.3041840.26553038100
2.2512-2.27860.26711570.24663115100
2.2786-2.30750.28621820.24553115100
2.3075-2.33780.27521840.23883063100
2.3378-2.36990.28521730.24743078100
2.3699-2.40370.30641650.24353155100
2.4037-2.43960.30341560.24653065100
2.4396-2.47770.33641650.24873107100
2.4777-2.51830.34481720.24833057100
2.5183-2.56170.28661250.24543144100
2.5617-2.60830.27131570.24753107100
2.6083-2.65850.31891520.24363087100
2.6585-2.71270.32582040.23283069100
2.7127-2.77170.31921610.23823092100
2.7717-2.83620.29311820.2246309699
2.8362-2.90710.29411770.22723077100
2.9071-2.98570.29511420.24133147100
2.9857-3.07350.23151780.21153062100
3.0735-3.17270.23962110.22053038100
3.1727-3.28610.29871700.21873105100
3.2861-3.41760.31171320.21363115100
3.4176-3.5730.27471480.19613126100
3.573-3.76130.24871580.1923126100
3.7613-3.99680.23851720.18563071100
3.9968-4.30520.22991610.18373109100
4.3052-4.7380.20531450.16893120100
4.738-5.42250.25821560.18693107100
5.4225-6.82770.28241770.22793081100
6.8277-44.1020.23941660.247297096
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)
10.19210.19210.05250.47680.10730.23180.2073-0.1340.10840.3068-0.0720.21910.13870.29340.03970.0970.0328-0.0280.0050.02340.123657.245-3.47393.721
20.3958-0.0215-0.10910.33810.23440.3027-0.02730.1247-0.08140.0443-0.0435-0.028-0.00460.027-0.05730.05220.0069-0.00260.05450.00630.096849.473-9.96670.517
30.2850.0816-0.12570.25190.00320.1287-0.06570.4043-0.17710.10460.16330.1001-0.0689-0.0570.11510.1005-0.0034-0.02230.24780.05530.043255.954-2.48840.597
40.07170.0584-0.03620.2357-0.21630.104-0.0217-0.0083-0.04180.29190.0064-0.1004-0.14230.035-0.01760.11830.0462-0.03710.0221-0.03470.078279.5433.46393.701
50.4352-0.12290.14310.3302-0.23890.19060.02730.0389-0.01880.0349-0.0045-0.0695-0.01730.09470.00250.06130.0051-0.0060.07780.01740.094387.3339.95970.498
60.29190.03070.07560.05320.06360.06380.00570.37310.00680.03230.0804-0.05160.33230.00150.1030.18230.02620.00420.2435-0.00690.062780.7543.11140.881
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 560:644 )A560 - 644
2X-RAY DIFFRACTION2( CHAIN A AND RESID 645:832 )A645 - 832
3X-RAY DIFFRACTION3( CHAIN A AND RESID 833:963 )A833 - 963
4X-RAY DIFFRACTION4( CHAIN B AND RESID 560:644 )B560 - 644
5X-RAY DIFFRACTION5( CHAIN B AND RESID 645:832 )B645 - 832
6X-RAY DIFFRACTION6( CHAIN B AND RESID 833:963 )B833 - 963

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