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- PDB-4pl5: Crystal structure of murine IRE1 in complex with OICR573 inhibitor -

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Basic information

Entry
Database: PDB / ID: 4pl5
TitleCrystal structure of murine IRE1 in complex with OICR573 inhibitor
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / Schiff base / hydroxy aryl aldehydes (HAA) / inhibitor complex / unfolded protein response / endoribonuclease / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


IRE1alpha activates chaperones / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / IRE1-TRAF2-ASK1 complex / positive regulation of ERAD pathway / insulin metabolic process / 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 ...IRE1alpha activates chaperones / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / IRE1-TRAF2-ASK1 complex / positive regulation of ERAD pathway / insulin metabolic process / 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 / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to vascular endothelial growth factor stimulus / endoplasmic reticulum unfolded protein response / positive regulation of JUN kinase activity / positive regulation of vascular associated smooth muscle cell proliferation / 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 / endonuclease activity / protein autophosphorylation / negative regulation of translation / 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 / protein homodimerization activity / mitochondrion / ATP binding
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. / 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 / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-31L / ADENOSINE-5'-DIPHOSPHATE / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.4 Å
AuthorsSanches, M. / Duffy, N. / Talukdar, M. / Thevakumaran, N. / Chiovitti, D. / Al-awar, R. / Patterson, J.B. / Sicheri, F.
Funding support Canada, United States, 3items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)MOP 84370 Canada
Multiple Myeloma Research Foundation Biotech Investment Award United States
Canadian Cancer Society Canada
CitationJournal: Nat Commun / Year: 2014
Title: Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.
Authors: Sanches, M. / Duffy, N.M. / Talukdar, M. / Thevakumaran, N. / Chiovitti, D. / Canny, M.D. / Lee, K. / Kurinov, I. / Uehling, D. / Al-Awar, R. / Poda, G. / Prakesch, M. / Wilson, B. / Tam, V. ...Authors: Sanches, M. / Duffy, N.M. / Talukdar, M. / Thevakumaran, N. / Chiovitti, D. / Canny, M.D. / Lee, K. / Kurinov, I. / Uehling, D. / Al-Awar, R. / Poda, G. / Prakesch, M. / Wilson, B. / Tam, V. / Schweitzer, C. / Toro, A. / Lucas, J.L. / Vuga, D. / Lehmann, L. / Durocher, D. / Zeng, Q. / Patterson, J.B. / Sicheri, F.
History
DepositionMay 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: entity_src_gen / pdbx_database_related ...entity_src_gen / pdbx_database_related / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / pdbx_struct_oper_list / software / struct_keywords
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_related.content_type ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_database_related.content_type / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text
Revision 1.3Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine_hist / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)204,65214
Polymers201,3264
Non-polymers3,32710
Water00
1
B: Serine/threonine-protein kinase/endoribonuclease IRE1
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,0878
Polymers100,6632
Non-polymers2,4246
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Serine/threonine-protein kinase/endoribonuclease IRE1
D: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,5666
Polymers100,6632
Non-polymers9034
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)319.220, 63.030, 140.780
Angle α, β, γ (deg.)90.000, 99.490, 90.000
Int Tables number5
Space group name H-MC121
Detailsbiological unit is the same as asym.

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Components

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


Mass: 50331.383 Da / Num. of mol.: 4 / Fragment: UNP residues 550-977
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ern1, Ire1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9EQY0, non-specific serine/threonine protein kinase, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-31L / 3-methoxy-5-methyl-4'-(morpholin-4-yl)biphenyl-4-ol


Mass: 299.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21NO3
#5: Chemical ChemComp-PEU / 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80-HEPTACOSAOXADOOCTACONTAN-82-OL / PEG 8000


Mass: 1221.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C55H112O28 / Comment: precipitant*YM
Nonpolymer detailsTHE 31L LIGAND REPRESENTS THE FINAL BOUND PRODUCT. THE STARTING MATERIAL FOR 31L LIGAND IS 2- ...THE 31L LIGAND REPRESENTS THE FINAL BOUND PRODUCT. THE STARTING MATERIAL FOR 31L LIGAND IS 2-HYDROXY-3-METHOXY-5-[4-(MORPHOLIN-4-YL)PHENYL]BENZALDEHYDE. ALDEHYDE IS ELIMINATED THROUGH THE FORMATION OF A SCHIFF-BASE WITH ONE OF THE PROTEIN'S LYSINE RESIDUES.

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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: 3.47 Å3/Da / Density % sol: 64.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M HEPES, 12% PEG8000, 8% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 3.4→48.27 Å / Num. obs: 36765 / % possible obs: 94.5 % / Redundancy: 3.71 % / Biso Wilson estimate: 57.16 Å2 / Net I/σ(I): 8.69
Reflection shellResolution: 3.4→3.6 Å / Redundancy: 3.71 % / Mean I/σ(I) obs: 1.74 / % possible all: 97.3

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.38 Å48.27 Å
Translation5.38 Å48.27 Å

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Processing

Software
NameVersionClassification
XDS2.5.0data reduction
PDB_EXTRACT3.14data extraction
PHASERphasing
PHENIX(phenix.refine: dev_1175)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PL3

4pl3


Resolution: 3.4→48.267 Å / FOM work R set: 0.7489 / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 31.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2852 1206 4.13 %
Rwork0.2219 27995 -
obs0.2247 29201 75.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 210.89 Å2 / Biso mean: 80.94 Å2 / Biso min: 5.6 Å2
Refinement stepCycle: final / Resolution: 3.4→48.267 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12464 0 165 0 12629
Biso mean--73.77 --
Num. residues----1540
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00612944
X-RAY DIFFRACTIONf_angle_d1.17817506
X-RAY DIFFRACTIONf_chiral_restr0.0831883
X-RAY DIFFRACTIONf_plane_restr0.0052235
X-RAY DIFFRACTIONf_dihedral_angle_d18.3574819
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.4-3.53290.3136390.33421011105025
3.5329-3.69370.452510.29021158120940
3.6937-3.88830.35231060.25622388249459
3.8883-4.13180.35691320.24893125325776
4.1318-4.45060.29711660.22063838400493
4.4506-4.89810.26331620.20064122428499
4.8981-5.6060.26781660.217641354301100
5.606-7.05940.26661850.224541584343100
7.0594-48.27150.24731990.1964060425995
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)
10.02060.0109-0.01890.016-0.00810.0392-0.0191-0.1117-0.05570.0778-0.0476-0.10.00230.0816-0.01650.1761-0.059-0.20850.53940.50390.029236.5511-12.729930.2719
20.1759-0.03950.09450.2883-0.10260.3886-0.07160.03980.084-0.0046-0.1472-0.0276-0.09710.1329-0.44830.05460.0728-0.02870.17130.080.024716.3324-3.798514.5247
30.115-0.1059-0.02390.11040.02640.1408-0.1016-0.0532-0.02920.0806-0.01130.04-0.0148-0.004-0.23880.09220.08520.01660.05560.00170.0606-5.633-8.454915.0968
40.01520.0035-0.00480.0095-0.00920.0070.00090.05180.033-0.00550.02150.04050.0085-0.0586-0.02080.30450.0083-0.12530.58090.48940.536427.9831-23.653955.8416
50.0006-0.00090.00090.0052-0.00770.0076-0.01130.0033-0.0067-0.0231-0.00190.0139-0.02450.0061-0.00450.20090.018-0.05640.36870.2540.286925.7392-23.805155.8266
60.02550.01080.00520.0143-0.01280.01930.01870.01520.0310.01720.05620.0461-0.0331-0.04290.13680.18120.13280.10220.13080.29120.336244.6856-25.407762.4299
70.012-0.006-0.00380.01390.00870.0078-0.00710.00580.00190.0358-0.01120.01770.01530.0069-0.04530.15580.0533-0.01740.1570.1810.124930.5617-24.605469.5057
80.0699-0.00680.00580.0799-0.02340.04810.0872-0.05090.05140.0440.02160.0449-0.0887-0.01880.3950.0549-0.00090.1012-0.17020.18170.142152.3148-23.109978.886
90.12660.08560.06520.06060.03880.03650.1769-0.0695-0.02120.1185-0.0428-0.0268-0.02010.0270.22720.2751-0.05080.110.01350.07080.296574.9082-18.565276.6798
100.04320.0028-0.00210.021-0.01510.0248-0.00180.06620.0711-0.06410.02310.10930.0423-0.0925-0.110.1816-0.1649-0.10090.44660.46070.25749.08718.540173.9899
110.0410.0012-0.00440.0174-0.0020.0188-0.0046-0.0333-0.02920.008-0.0087-0.01570.0553-0.037-0.00180.1856-0.2060.03330.22610.31560.146519.3676.500692.8862
120.043-0.01850.00080.01950.00590.0176-0.038-0.0326-0.0104-0.1076-0.0382-0.05530.06580.0536-0.08910.2888-0.19310.09920.25710.23010.247812.1231-6.6105111.2263
130.03590.01460.00960.4455-0.01050.0962-0.04480.11540.0402-0.13120.0517-0.05950.02280.12130.2930.1862-0.13030.0170.93850.40290.310138.9691-7.7991140.4885
140.0069-0.0046-0.00770.0133-0.00160.02330.06250.00840.0367-0.04950.0567-0.11110.02460.160.00050.8058-0.18920.13790.65860.23850.659342.23221.694104.5491
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 562 through 737 )B0
2X-RAY DIFFRACTION2chain 'B' and (resid 738 through 862 )B0
3X-RAY DIFFRACTION3chain 'B' and (resid 863 through 963 )B0
4X-RAY DIFFRACTION4chain 'A' and (resid 562 through 627 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 628 through 648 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 649 through 706 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 707 through 736 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 737 through 862 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 863 through 964 )A0
10X-RAY DIFFRACTION10chain 'C' and (resid 562 through 752 )C0
11X-RAY DIFFRACTION11chain 'C' and (resid 753 through 849 )C0
12X-RAY DIFFRACTION12chain 'C' and (resid 850 through 963 )C0
13X-RAY DIFFRACTION13chain 'D' and (resid 561 through 849 )D0
14X-RAY DIFFRACTION14chain 'D' and (resid 850 through 963 )D0

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