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- PDB-7bmk: ATP-Competitive Partial Antagonists-'PAIR's-Rheostatically Modula... -

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Basic information

Entry
Database: PDB / ID: 7bmk
TitleATP-Competitive Partial Antagonists-'PAIR's-Rheostatically Modulate IRE1alpha's Kinase Helix-alphaC to Segregate its RNase-Mediated Biological Outputs
ComponentsSerine/threonine-protein kinase/endoribonuclease IRE1
KeywordsUNKNOWN FUNCTION / Kinase / kinase inhibitor / transferase / transferase 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 / 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
DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Chem-U4N / Serine/threonine-protein kinase/endoribonuclease IRE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsFeldman, H.C. / Ghosh, R. / Auyeung, V. / Mueller, J.L. / Vidadala, V.N. / Olivier, A. / Backes, B.J. / Zikherman, J. / Papa, F.R. / Maly, D.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK100623 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)U01DK123609 United States
CitationJournal: Nat.Chem.Biol. / Year: 2021
Title: ATP-competitive partial antagonists of the IRE1 alpha RNase segregate outputs of the UPR.
Authors: Feldman, H.C. / Ghosh, R. / Auyeung, V.C. / Mueller, J.L. / Kim, J.H. / Potter, Z.E. / Vidadala, V.N. / Perera, B.G.K. / Olivier, A. / Backes, B.J. / Zikherman, J. / Papa, F.R. / Maly, D.J.
History
DepositionJan 20, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 19, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_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)102,91738
Polymers99,1252
Non-polymers3,79236
Water11,331629
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10040 Å2
ΔGint90 kcal/mol
Surface area37090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.903, 72.813, 119.239
Angle α, β, γ (deg.)90.000, 129.820, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1292-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: _ / Auth seq-ID: 562 - 963 / Label seq-ID: 19 - 420

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Serine/threonine-protein kinase/endoribonuclease IRE1 / Endoplasmic reticulum-to-nucleus signaling 1 / Inositol-requiring protein 1 / hIRE1p / Ire1-alpha / IRE1a


Mass: 49562.590 Da / Num. of mol.: 2 / Fragment: KINASE AND NUCLEASE DOMAIN
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

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Non-polymers , 6 types, 665 molecules

#2: Chemical ChemComp-U4N / 2,2,2-tris(fluoranyl)-~{N}-[4-[3-[2-[[(3~{S})-piperidin-3-yl]amino]pyrimidin-4-yl]pyridin-2-yl]oxynaphthalen-1-yl]ethanesulfonamide


Mass: 558.575 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H25F3N6O3S
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 629 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.01 Å3/Da / Density % sol: 59.16 %
Crystal growTemperature: 279 K / Method: vapor diffusion / pH: 6
Details: 10.00 %v/v 2-PropOH 13.00 %w/v PEG 4K 0.10 M Na3 Cit

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 31, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 1.85→91.59 Å / Num. obs: 91213 / % possible obs: 98.1 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.037 / Net I/σ(I): 17.89
Reflection shellResolution: 1.85→2.1 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.43 / Num. unique obs: 28858 / % possible all: 98.6

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.85→91.59 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.946 / SU B: 4.348 / SU ML: 0.106 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.127 / ESU R Free: 0.127 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.235 2411 2.6 %RANDOM
Rwork0.1911 ---
obs0.1922 88799 98.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 142.59 Å2 / Biso mean: 42.17 Å2 / Biso min: 15.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.63 Å20 Å2-0.08 Å2
2---0.43 Å20 Å2
3----0.03 Å2
Refinement stepCycle: final / Resolution: 1.85→91.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6461 0 252 641 7354
Biso mean--57.12 46.25 -
Num. residues----798
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0196927
X-RAY DIFFRACTIONr_bond_other_d0.0050.026554
X-RAY DIFFRACTIONr_angle_refined_deg1.6231.989345
X-RAY DIFFRACTIONr_angle_other_deg1.303315068
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2425847
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.70123.333321
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.688151134
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9011550
X-RAY DIFFRACTIONr_chiral_restr0.1010.21002
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217722
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021622
Refine LS restraints NCS

Ens-ID: 1 / Number: 9320 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.04 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.85→1.898 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.463 194 -
Rwork0.462 6585 -
all-6779 -
obs--99.08 %
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)
16.34380.3344-3.32050.7237-0.2174.7470.1240.11620.05160.1647-0.02150.2638-0.221-0.4745-0.10250.0887-0.02070.04050.0991-0.01110.2224.07-6.05342.289
23.22560.13681.01682.48040.69464.49070.08450.407-0.0958-0.23680.2087-0.26970.05160.6866-0.29330.02750.00260.01930.1599-0.07070.04752.888-2.61923.553
38.50940.241-2.26630.64790.26743.0630.0192-0.25440.298-0.0390.09480.3927-0.0683-0.4939-0.1140.12130.02070.04340.2480.06640.354-2.121-20.20726.302
42.43510.2345-0.06993.17210.7724.13720.05370.1212-0.068-0.01290.1662-0.47170.34850.373-0.21980.0921-0.02970.02210.1151-0.06850.089446.33-19.5214.869
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A561 - 645
2X-RAY DIFFRACTION2A831 - 963
3X-RAY DIFFRACTION3B562 - 645
4X-RAY DIFFRACTION4B831 - 963

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