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- PDB-4pl3: Crystal structure of murine IRE1 in complex with MKC9989 inhibitor -

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Basic information

Entry
Database: PDB / ID: 4pl3
TitleCrystal structure of murine IRE1 in complex with MKC9989 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 / 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 ...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 / 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 / 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 / RNA endonuclease activity / Hsp70 protein binding / positive regulation of RNA splicing / cellular response to glucose stimulus / Hsp90 protein binding / ADP binding / cellular response to hydrogen peroxide / unfolded protein binding / endonuclease activity / protein autophosphorylation / non-specific serine/threonine protein kinase / negative regulation of translation / 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-31J / ADENOSINE-5'-DIPHOSPHATE / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.9 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: Advisory / Derived calculations ...Advisory / Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_database_status ...entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / pdbx_validate_close_contact / pdbx_validate_symm_contact / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation
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.number_atoms_total / _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
A: Serine/threonine-protein kinase/endoribonuclease IRE1
B: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,2108
Polymers100,6632
Non-polymers1,5486
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2300 Å2
ΔGint-32 kcal/mol
Surface area37160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)246.080, 90.500, 72.130
Angle α, β, γ (deg.)90.00, 91.88, 90.00
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.: 2 / Fragment: UNP residues 550-977 / Mutation: N230Y
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-31J / 7-hydroxy-6-methoxy-3-[2-(2-methoxyethoxy)ethyl]-4,8-dimethyl-2H-chromen-2-one


Mass: 322.353 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H22O6
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
Nonpolymer detailsTHE 31J LIGAND REPRESENTS THE FINAL BOUND PRODUCT. THE STARTING MATERIAL FOR 31J LIGAND IS 7- ...THE 31J LIGAND REPRESENTS THE FINAL BOUND PRODUCT. THE STARTING MATERIAL FOR 31J LIGAND IS 7-HYDROXY-6-METHOXY-3-[2-(2-METHOXYETHOXY)ETHYL]-4-METHYL-2-OXO-2H-CHROMENE-8-CARBALDEHYDE. 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: 3.99 Å3/Da / Density % sol: 69.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M HEPES, 12% PEG8000, 8% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 7, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.9→72.09 Å / Num. obs: 21893 / % possible obs: 96.2 % / Observed criterion σ(I): -3 / Redundancy: 3.69 % / Biso Wilson estimate: 38.76 Å2 / Rmerge F obs: 0.356 / Rmerge(I) obs: 0.131 / Rrim(I) all: 0.153 / Χ2: 1.086 / Net I/σ(I): 7.14 / Num. measured all: 125401
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.9-2.981.7270.8461.178586257225640.99899.7
2.98-3.061.4720.7211.559306253225220.84199.6
3.06-3.151.1470.532.219448247324650.61699.7
3.15-3.241.0380.4552.668968236323490.53299.4
3.24-3.350.8450.3883.368830233723160.45499.1
3.35-3.470.7310.3084.427482224520970.36693.4
3.47-3.60.6750.2564.927972217821240.29997.5
3.6-3.740.5460.2185.766132207318240.26188
3.74-3.910.4020.1626.756405199217960.19190.2
3.91-4.10.3580.1477.866461192117840.17392.9
4.1-4.320.2340.1089.466698181817680.12597.2
4.32-4.590.1930.10310.26342173716920.1297.4
4.59-4.90.1490.0911.525870160615590.10597.1
4.9-5.290.1360.09111.535596152714770.10696.7
5.29-5.80.1210.0912.125117138313310.10496.2
5.8-6.480.1070.0813.054662128212260.09295.6
6.48-7.490.0710.06515.274020111210590.07595.2
7.49-9.170.0470.04918.9733739659100.05794.3
9.17-12.970.0290.04422.9627207507020.0593.6
12.970.0240.0423.4714134243740.04688.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.9 Å72.09 Å
Translation2.9 Å72.09 Å

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: dev_1175)refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.14data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P23

3p23


Resolution: 2.9→72.091 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 24.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2336 457 2.09 %
Rwork0.2014 --
obs0.2021 21855 61.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: final / Resolution: 2.9→72.091 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6228 0 126 0 6354
Biso mean--41.86 --
Num. residues----771
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0176497
X-RAY DIFFRACTIONf_angle_d1.3848797
X-RAY DIFFRACTIONf_dihedral_angle_d19.7592397
X-RAY DIFFRACTIONf_chiral_restr0.07943
X-RAY DIFFRACTIONf_plane_restr0.0071119
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9001-3.31970.3965690.29863355X-RAY DIFFRACTION29
3.3197-4.18240.25011470.22567052X-RAY DIFFRACTION62
4.1824-72.11330.20582410.174710991X-RAY DIFFRACTION94
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)
12.8969-0.7388-1.05271.3168-0.24823.2201-0.03250.10650.41320.09040.08590.0953-0.4015-0.27830.02770.19690.0295-0.0440.34390.01650.376612.43733.17839.275
22.82970.9172-0.57841.403-0.11061.9438-0.1123-0.01240.0622-0.22140.08220.0334-0.48140.2111-0.03870.3411-0.2052-0.01760.1526-0.00410.189646.160137.504626.3892
32.602-0.68960.53810.9276-0.7083.14680.04020.0427-0.4483-0.06430.040.3050.3264-0.7859-0.12060.2106-0.0092-0.01810.4057-0.00350.342812.449319.4629-6.9769
42.1711-1.09951.31851.0917-0.57742.90260.00580.1254-0.2009-0.0410.0191-0.04560.58610.0959-0.03230.30030.16370.02930.24310.03010.258843.18838.36848.4969
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 560 through 644 )
2X-RAY DIFFRACTION2chain 'A' and (resid 645 through 964 )
3X-RAY DIFFRACTION3chain 'B' and (resid 562 through 644)
4X-RAY DIFFRACTION4chain 'B' and (resid 645 through 963 )

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