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- PDB-8uvl: Crystal structure of selective IRE1a inhibitor 29 at the enzyme a... -

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Basic information

Entry
Database: PDB / ID: 8uvl
TitleCrystal structure of selective IRE1a inhibitor 29 at the enzyme active site
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsTRANSFERASE/INHIBITOR / kinase / cancer / Multiple Myeloma / selective / 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 / 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 / endothelial cell proliferation / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / 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
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 / Quinoprotein alcohol dehydrogenase-like superfamily / Serine/threonine-protein kinase, active site ...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 / Quinoprotein alcohol dehydrogenase-like superfamily / 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
Similarity search - Domain/homology
: / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsKiefer, J.R. / Wallweber, H.A. / Braun, M.-G. / Wei, W. / Jiang, F. / Wang, W. / Rudolph, J. / Ashkenazi, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Potent, Selective, and Orally Available IRE1 alpha Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.
Authors: Braun, M.G. / Ashkenazi, A. / Beveridge, R.E. / Castanedo, G. / Wallweber, H.A. / Beresini, M.H. / Clark, K.R. / De Bruyn, T. / Fu, L. / Gibbons, P. / Jiang, F. / Kaufman, S. / Kan, D. / ...Authors: Braun, M.G. / Ashkenazi, A. / Beveridge, R.E. / Castanedo, G. / Wallweber, H.A. / Beresini, M.H. / Clark, K.R. / De Bruyn, T. / Fu, L. / Gibbons, P. / Jiang, F. / Kaufman, S. / Kan, D. / Kiefer, J.R. / Leclerc, J.P. / Lemire, A. / Ly, C. / Segal, E. / Sims, J. / Wang, W. / Wei, W. / Zhao, L. / Schwarz, J.B. / Rudolph, J.
History
DepositionNov 3, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,45810
Polymers51,3721
Non-polymers1,0859
Water1,38777
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.890, 166.834, 102.950
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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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: 51372.477 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 multiple nucleopolyhedrovirus
References: UniProt: O75460, non-specific serine/threonine protein kinase, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-XOE / 1-phenyl-N-(2,3,6-trifluoro-4-{[(3M)-3-(2-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrimidin-4-yl)pyridin-2-yl]oxy}phenyl)methanesulfonamide


Mass: 588.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24F4N6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.84 Å3/Da / Density % sol: 56.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5
Details: 89mM HEPES pH 7.5, 32% PEG 200, 3% 6-aminohexanoic acid, 100mM lithium chloride

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Data collection

DiffractionMean temperature: 193 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.43→43.81 Å / Num. obs: 22437 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 64.12 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.025 / Rrim(I) all: 0.065 / Χ2: 1.14 / Net I/σ(I): 20.4 / Num. measured all: 147282
Reflection shellResolution: 2.43→2.52 Å / % possible obs: 100 % / Redundancy: 6.5 % / Rmerge(I) obs: 1.038 / Num. measured all: 15096 / Num. unique obs: 2319 / CC1/2: 0.798 / Rpim(I) all: 0.439 / Rrim(I) all: 1.128 / Χ2: 1.02 / Net I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.43→32.41 Å / SU ML: 0.3431 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.138
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.251 1100 4.91 %
Rwork0.1808 21309 -
obs0.184 22409 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.76 Å2
Refinement stepCycle: LAST / Resolution: 2.43→32.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3206 0 73 77 3356
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00823354
X-RAY DIFFRACTIONf_angle_d1.0774524
X-RAY DIFFRACTIONf_chiral_restr0.0592485
X-RAY DIFFRACTIONf_plane_restr0.0086582
X-RAY DIFFRACTIONf_dihedral_angle_d27.5145459
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.43-2.540.33291450.26452590X-RAY DIFFRACTION99.89
2.54-2.670.30971420.24262615X-RAY DIFFRACTION100
2.67-2.840.34451470.25572640X-RAY DIFFRACTION99.96
2.84-3.060.28761190.21952642X-RAY DIFFRACTION100
3.06-3.370.30481590.2272630X-RAY DIFFRACTION99.96
3.37-3.860.24821230.17432684X-RAY DIFFRACTION100
3.86-4.860.23151360.14392705X-RAY DIFFRACTION100
4.86-32.410.20151290.16482803X-RAY DIFFRACTION99.56
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)
11.81634686636-0.5834426143040.7503364891381.397852450050.003428895405781.04165234358-0.1632297157330.2426376126710.782743508136-0.355764880580.03764322854780.0615390335177-0.9543222651110.2266428227489.85751358758E-51.03883687176-0.0748394451007-0.05695622337640.741735716866-0.03408965934290.96596385379910.305577630941.441695840322.7213364962
23.312680451640.0169894578954-0.6800143529971.878729139630.6040779940872.02587947319-0.09200917745550.1111572525130.0420191563128-0.135528822891-0.0263983402634-0.0849991494211-0.2403721819740.264344743411-0.0002658590777310.532919491078-0.0383612657123-0.07483440340730.6038261371910.01338795475830.6055150682818.615175921822.689417053416.3753838961
30.08356547291550.00496887369493-0.0270616381361-0.000811349740218-0.002660179546510.01141198230820.1664617084020.216158622284-0.462715711121.04051779533-0.281175667078-0.653015762284-0.03248292460191.1371215342-0.003003506243430.7994438732020.104403191486-0.0700023450870.9605826004130.06359729745150.81950308308630.1999897926.3686076764719.0815151193
41.750117916460.288402151266-0.125502924163.476967725440.01061686521891.97084018382-0.250456445748-0.13306002452-0.308788785990.332353162870.04948519028840.127701055320.5461247462970.00420548323961-0.0001235243902750.7240391844250.06847114416580.122621938560.6530819444420.02692019765160.64798467728313.6767906078-6.5986750343120.8475114283
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 562 through 646 )562 - 6461 - 85
22chain 'A' and (resid 647 through 787 )647 - 78786 - 226
33chain 'A' and (resid 788 through 799 )788 - 799227 - 238
44chain 'A' and (resid 800 through 964 )800 - 964239 - 403

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