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- PDB-4z7h: Crystal structure of human IRE1 cytoplasmic kinase-RNase region -... -

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Basic information

Entry
Database: PDB / ID: 4z7h
TitleCrystal structure of human IRE1 cytoplasmic kinase-RNase region - complex with imidazopyridine compound 3
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE / kinase / RNase / unfolded protein response
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-4L5 / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsJoshi, A. / Bayliss, R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC24461/A13231 United Kingdom
CitationJournal: Oncotarget / Year: 2015
Title: Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.
Authors: Joshi, A. / Newbatt, Y. / McAndrew, P.C. / Stubbs, M. / Burke, R. / Richards, M.W. / Bhatia, C. / Caldwell, J.J. / McHardy, T. / Collins, I. / Bayliss, R.
History
DepositionApr 7, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Database references
Revision 1.2Oct 9, 2019Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_DOI
Revision 1.3Jan 10, 2024Group: 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)96,2585
Polymers95,5122
Non-polymers7473
Water37821
1
A: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,1773
Polymers47,7561
Non-polymers4212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase/endoribonuclease IRE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0812
Polymers47,7561
Non-polymers3251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.678, 81.957, 168.682
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 47755.820 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-4L5 / 2-methoxy-4-[6-(propan-2-ylamino)imidazo[1,2-b]pyridazin-3-yl]benzamide


Mass: 325.365 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C17H19N5O2 / Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.83 Å3/Da / Density % sol: 56.52 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: Apo-hIRE1 was crystallized by hanging-drop vapor diffusion by mixing IRE1 (at 2 mg/mL) with reservoir solution containing 18-20% PEG3350, 0.2 M sodium malonate and 0.1 Bis-Trispropane (pH 6. ...Details: Apo-hIRE1 was crystallized by hanging-drop vapor diffusion by mixing IRE1 (at 2 mg/mL) with reservoir solution containing 18-20% PEG3350, 0.2 M sodium malonate and 0.1 Bis-Trispropane (pH 6.5) in a 1:1 ratio. Crystals were briefly (30 sec) soaked in 22% PEG3350, 0.2 M Na Malonate, 0.1 M Bis-Trispropane (pH 7.5) and 25% ethylene glycol before plunging into liquid N2.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 24, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.9→46.36 Å / Num. obs: 24770 / % possible obs: 99.7 % / Redundancy: 6.6 % / Biso Wilson estimate: 79.38 Å2 / Rmerge(I) obs: 0.201 / Net I/σ(I): 7.5
Reflection shellResolution: 2.9→3.08 Å / Redundancy: 6.4 % / Rmerge(I) obs: 1.44 / Mean I/σ(I) obs: 1.4 / % possible all: 99

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Processing

Software
NameVersionClassification
BUSTER2.10.1refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Z7G

4z7g


Resolution: 2.9→46.36 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.905 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.321
RfactorNum. reflection% reflectionSelection details
Rfree0.2248 1260 5.09 %RANDOM
Rwork0.2002 ---
obs0.2015 24770 99.55 %-
Displacement parametersBiso mean: 86.73 Å2
Baniso -1Baniso -2Baniso -3
1-17.1244 Å20 Å20 Å2
2---1.469 Å20 Å2
3----15.6554 Å2
Refine analyzeLuzzati coordinate error obs: 0.451 Å
Refinement stepCycle: 1 / Resolution: 2.9→46.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6186 0 5 21 6212
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016428HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.148710HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2275SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes144HARMONIC2
X-RAY DIFFRACTIONt_gen_planes929HARMONIC5
X-RAY DIFFRACTIONt_it6428HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.43
X-RAY DIFFRACTIONt_other_torsion21.08
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion801SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7328SEMIHARMONIC4
LS refinement shellResolution: 2.9→3.03 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2662 145 4.95 %
Rwork0.2322 2783 -
all0.2339 2928 -
obs--99.55 %
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)
14.5215-0.3461-1.81215.4284-2.73187.7804-0.0291-0.8448-0.03940.75460.1511-0.36740.26950.4391-0.122-0.04990.0975-0.0658-0.0275-0.0446-0.187834.3485-8.190617.7582
26.2112-2.1913-0.10783.60610.07782.22470.10060.1390.25890.0898-0.061-0.49870.17770.0316-0.0397-0.23-0.0028-0.0192-0.19380.0503-0.070240.8535-10.56750.0416
32.7868-1.21241.67613.0317-0.66485.26220.48211.04590.4847-0.7241-0.5287-0.0574-0.0180.00120.0466-0.28130.26750.07710.2150.1621-0.35341.0143-10.6621-26.6315
45.16011.39561.23268.44790.54784.6057-0.0959-1.02390.0490.98990.17340.5174-0.5499-0.3917-0.0776-0.03750.14880.10690.0221-0.0281-0.251419.56768.836118.1706
55.9291-0.23940.75312.17390.11922.6689-0.21140.0740.03120.2720.08430.109-0.11540.02780.1271-0.22720.02960.0434-0.19210.0278-0.052712.385410.97450.6523
62.4056-0.7558-1.36542.46140.8355.96170.12451.0487-0.1538-0.5308-0.1230.11040.2731-0.3543-0.0015-0.31150.0814-0.07760.129-0.0089-0.20589.19068.7821-26.7996
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|563 - 642}
2X-RAY DIFFRACTION2{A|643 - 769}
3X-RAY DIFFRACTION3{A|770 - 962}
4X-RAY DIFFRACTION4{B|563 - 642}
5X-RAY DIFFRACTION5{B|643 - 769}
6X-RAY DIFFRACTION6{B|770 - 962}

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