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- PDB-6hv0: IRE1 kinase/RNase in complex with imidazo[1,2-b]pyridazin-8-amine... -

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Basic information

Entry
Database: PDB / ID: 6hv0
TitleIRE1 kinase/RNase in complex with imidazo[1,2-b]pyridazin-8-amine compound 33
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsSIGNALING PROTEIN / Unfolded Protein Response Allosteric inhibitor
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 / positive regulation of endoplasmic reticulum unfolded protein response / peptidyl-serine autophosphorylation / 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 / positive regulation of endoplasmic reticulum unfolded protein response / peptidyl-serine autophosphorylation / platelet-derived growth factor receptor binding / IRE1-RACK1-PP2A complex / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / endothelial cell proliferation / nuclear inner membrane / IRE1-mediated unfolded protein response / mRNA catabolic process / positive regulation of JUN kinase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to vascular endothelial growth factor stimulus / regulation of macroautophagy / cellular response to unfolded protein / 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 / Hsp90 protein binding / cellular response to glucose stimulus / ADP binding / cellular response to hydrogen peroxide / unfolded protein binding / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / 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 / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / de novo design (two linked rop proteins) ...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 / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / de novo design (two linked rop proteins) / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / 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-GUK / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsBayliss, R. / Bhatia, C. / Collins, I.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
Cancer Research UKC24461/A13231 United Kingdom
Cancer Research UKC24461/A12772 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2019
Title: Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1 alpha Kinase-Endoribonuclease.
Authors: Colombano, G. / Caldwell, J.J. / Matthews, T.P. / Bhatia, C. / Joshi, A. / McHardy, T. / Mok, N.Y. / Newbatt, Y. / Pickard, L. / Strover, J. / Hedayat, S. / Walton, M.I. / Myers, S.M. / ...Authors: Colombano, G. / Caldwell, J.J. / Matthews, T.P. / Bhatia, C. / Joshi, A. / McHardy, T. / Mok, N.Y. / Newbatt, Y. / Pickard, L. / Strover, J. / Hedayat, S. / Walton, M.I. / Myers, S.M. / Jones, A.M. / Saville, H. / McAndrew, C. / Burke, R. / Eccles, S.A. / Davies, F.E. / Bayliss, R. / Collins, I.
History
DepositionOct 9, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 24, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0832
Polymers47,7561
Non-polymers3271
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.040, 46.050, 86.340
Angle α, β, γ (deg.)90.00, 112.71, 90.00
Int Tables number5
Space group name H-MC121

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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.: 1
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-GUK / 6-chloranyl-3-(2~{H}-indazol-5-yl)-~{N}-propan-2-yl-imidazo[1,2-b]pyridazin-8-amine


Mass: 326.784 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15ClN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O

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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: 2.77 Å3/Da / Density % sol: 55.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20% polyethylene glycol 3350, 0.2 M sodium acetate and 0.1 bis-tris propane (pH 6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Oct 4, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.73→40.4 Å / Num. obs: 14150 / % possible obs: 99.2 % / Redundancy: 3.5 % / CC1/2: 0.986 / Rrim(I) all: 0.167 / Net I/σ(I): 17.5
Reflection shellResolution: 2.73→2.86 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1770 / CC1/2: 0.584 / Rrim(I) all: 0.742 / % possible all: 94.8

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Z7G

4z7g


Resolution: 2.73→32.967 Å / SU ML: 0.37 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.18
RfactorNum. reflection% reflection
Rfree0.2689 1415 10 %
Rwork0.2116 --
obs0.2175 14143 99.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.73→32.967 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2998 0 23 57 3078
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043096
X-RAY DIFFRACTIONf_angle_d0.8444185
X-RAY DIFFRACTIONf_dihedral_angle_d14.0171139
X-RAY DIFFRACTIONf_chiral_restr0.031451
X-RAY DIFFRACTIONf_plane_restr0.004537
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7253-2.82260.34211290.31011162X-RAY DIFFRACTION92
2.8226-2.93560.32091420.27531269X-RAY DIFFRACTION99
2.9356-3.06910.31211410.2771268X-RAY DIFFRACTION100
3.0691-3.23080.31251390.23351267X-RAY DIFFRACTION100
3.2308-3.4330.26761430.22031276X-RAY DIFFRACTION100
3.433-3.69770.28881410.20541270X-RAY DIFFRACTION100
3.6977-4.06920.24121430.18931280X-RAY DIFFRACTION100
4.0692-4.65670.25211440.16631301X-RAY DIFFRACTION100
4.6567-5.86150.22961430.18921296X-RAY DIFFRACTION100
5.8615-32.96980.24051500.19621339X-RAY DIFFRACTION100

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