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- PDB-5ul1: The co-structure of 3-amino-6-(4-((1-(dimethylamino)propan-2-yl)s... -

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Entry
Database: PDB / ID: 5ul1
TitleThe co-structure of 3-amino-6-(4-((1-(dimethylamino)propan-2-yl)sulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide and a rationally designed PI3K-alpha mutant that mimics ATR
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/SIGNALING PROTEIN/INHIBITOR / inhibitor / lipid kinase / mutation / ATR / TRANSFERASE-SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / T follicular helper cell differentiation / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / myeloid leukocyte migration / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase regulatory subunit binding / regulation of cellular respiration / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / phosphatidylinositol 3-kinase complex, class IB / positive regulation of protein localization to membrane / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / RHOD GTPase cycle / cardiac muscle cell contraction / RHOF GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / kinase activator activity / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / positive regulation of leukocyte migration / relaxation of cardiac muscle / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / negative regulation of stress fiber assembly / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND1 GTPase cycle / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / RND2 GTPase cycle / vascular endothelial growth factor signaling pathway / RND3 GTPase cycle / phosphatidylinositol 3-kinase / insulin binding / growth hormone receptor signaling pathway / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / RHOB GTPase cycle / RHOV GTPase cycle / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / GP1b-IX-V activation signalling / negative regulation of macroautophagy / natural killer cell mediated cytotoxicity / PI-3K cascade:FGFR2 / response to dexamethasone / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / CDC42 GTPase cycle / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / T cell differentiation / intercalated disc / protein kinase activator activity / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / regulation of multicellular organism growth / negative regulation of cell-matrix adhesion / RHOA GTPase cycle / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / Role of LAT2/NTAL/LAB on calcium mobilization
Similarity search - Function
PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) ...PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / Rho GTPase activation protein / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / C2 domain / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-8DY / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3 Å
AuthorsKnapp, M.S. / Elling, R.A. / Mamo, M.
CitationJournal: J. Mol. Biol. / Year: 2017
Title: Rationally Designed PI3K alpha Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors.
Authors: Lu, Y. / Knapp, M. / Crawford, K. / Warne, R. / Elling, R. / Yan, K. / Doyle, M. / Pardee, G. / Zhang, L. / Ma, S. / Mamo, M. / Ornelas, E. / Pan, Y. / Bussiere, D. / Jansen, J. / Zaror, I. ...Authors: Lu, Y. / Knapp, M. / Crawford, K. / Warne, R. / Elling, R. / Yan, K. / Doyle, M. / Pardee, G. / Zhang, L. / Ma, S. / Mamo, M. / Ornelas, E. / Pan, Y. / Bussiere, D. / Jansen, J. / Zaror, I. / Lai, A. / Barsanti, P. / Sim, J.
History
DepositionJan 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,8263
Polymers160,3872
Non-polymers4401
Water2,936163
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6240 Å2
ΔGint-14 kcal/mol
Surface area54530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.431, 108.814, 136.576
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 125243.844 Da / Num. of mol.: 1 / Mutation: M232K L233K I800M F930V W780K V850W R770E E798I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: unidentified baculovirus
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit ...PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 35142.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: unidentified baculovirus / References: UniProt: P27986
#3: Chemical ChemComp-8DY / 3-amino-6-(4-{[(2S)-1-(dimethylamino)propan-2-yl]sulfonyl}phenyl)-N-phenylpyrazine-2-carboxamide


Mass: 439.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N5O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 163 / 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: 2.33 Å3/Da / Density % sol: 47.13 %
Crystal growTemperature: 303.15 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 3 UL OF PROTEIN WAS MIXED WITH 5 UL OF WELL SOLUTION CONTAINING 12% PEG 3350 AND 120 MM POTASSIUM THIOCYANATE, PH 7.2, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.95→47.13 Å / Num. obs: 31688 / % possible obs: 95 % / Redundancy: 5.9 % / Biso Wilson estimate: 76.17 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.045 / Rrim(I) all: 0.111 / Net I/σ(I): 17.4
Reflection shellResolution: 3.1→3.31 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.547 / CC1/2: 0.88 / Rpim(I) all: 0.24 / Rrim(I) all: 0.598 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTERrefinement
XDSdata reduction
Aimless0.5.29data scaling
PHASERphasing
PDB_EXTRACT3.22data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 3→47.13 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.865 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.464
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1461 5 %RANDOM
Rwork0.19 ---
obs0.193 29244 95.5 %-
Displacement parametersBiso max: 190.54 Å2 / Biso mean: 62.46 Å2 / Biso min: 15.78 Å2
Baniso -1Baniso -2Baniso -3
1-11.4516 Å20 Å20 Å2
2---3.1811 Å20 Å2
3----8.2705 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 3→47.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10182 0 31 163 10376
Biso mean--66.5 45.28 -
Num. residues----1257
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3724SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes287HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1497HARMONIC5
X-RAY DIFFRACTIONt_it10444HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1344SEMIHARMONIC5
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_contact12054SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d10444HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg14124HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.62
X-RAY DIFFRACTIONt_other_torsion19.46
LS refinement shellResolution: 3→3.1 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.319 151 5.11 %
Rwork0.24 2806 -
all0.244 2957 -
obs--99.97 %
Refinement TLS params.

L11: 0 °2 / L12: 0 °2 / L13: 0 °2 / L22: 0 °2 / L23: 0 °2 / L33: 0 °2 / S11: 0 Å ° / S12: 0 Å ° / S13: 0 Å ° / S21: 0 Å ° / S22: 0 Å ° / S23: 0 Å ° / S31: 0 Å ° / S32: 0 Å ° / S33: 0 Å ° / T11: 0 Å2 / T12: 0 Å2 / T13: 0 Å2 / T22: 0 Å2 / T23: 0 Å2 / T33: 0 Å2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDOrigin x (Å)Origin y (Å)Origin z (Å)
19.5313-27.3821-28.4536
215.2971-15.7402-49.614
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 1053
2X-RAY DIFFRACTION2{ B|* }B327 - 591

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