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- PDB-7mlk: Crystal structure of human PI3Ka (p110a subunit) with MMV085400 b... -

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Basic information

Entry
Database: PDB / ID: 7mlk
TitleCrystal structure of human PI3Ka (p110a subunit) with MMV085400 bound to the active site determined at 2.9 angstroms resolution
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/INHIBITOR / PI3K / pyrazine / complex / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of macroautophagy / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / response to dexamethasone / PI-3K cascade:FGFR2 / protein kinase activator activity / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / PI3K events in ERBB2 signaling / negative regulation of anoikis / intercalated disc / RET signaling / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / adipose tissue development / phagocytosis / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / energy homeostasis / positive regulation of lamellipodium assembly / Signaling by FGFR4 in disease / cardiac muscle contraction / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / Tie2 Signaling / GPVI-mediated activation cascade / Signaling by FGFR2 in disease / T cell costimulation / RAC1 GTPase cycle / response to muscle stretch / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / Regulation of signaling by CBL / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / regulation of protein phosphorylation / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / Signaling by SCF-KIT / platelet activation / VEGFA-VEGFR2 Pathway / cellular response to insulin stimulus / glucose metabolic process / Constitutive Signaling by Aberrant PI3K in Cancer
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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. / Phosphoinositide 3-kinase C2 ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-ZHY / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.91 Å
AuthorsKrake, S.H. / Martinez, P.D.G. / Poggi, M.L. / Ferreira, M.S. / Aguiar, A.C.C. / Souza, G.E. / Wenlock, M. / Jones, B. / Steinbrecher, T. / Day, T. ...Krake, S.H. / Martinez, P.D.G. / Poggi, M.L. / Ferreira, M.S. / Aguiar, A.C.C. / Souza, G.E. / Wenlock, M. / Jones, B. / Steinbrecher, T. / Day, T. / McPhail, J. / Burke, J. / Yeo, T. / Mok, S. / Uhlemann, A.C. / Fidock, D.A. / Chen, P. / Grodsky, N. / Deng, Y.L. / Guido, R.V.C. / Campbell, S.F. / Willis, P.A. / Dias, L.C.
Funding support Brazil, 1items
OrganizationGrant numberCountry
Other privateRD-12-0103 Brazil
CitationJournal: To Be Published
Title: Discovery of 2,6-disubstituted pyrazines as potent PI4K inhibitors with antimalarial activity
Authors: Krake, S.H. / Martinez, P.D.G. / Poggi, M.L. / Ferreira, M.S. / Aguiar, A.C.C. / Souza, G.E. / Wenlock, M. / Jones, B. / Steinbrecher, T. / Day, T. / McPhail, J. / Burke, J. / Yeo, T. / Mok, ...Authors: Krake, S.H. / Martinez, P.D.G. / Poggi, M.L. / Ferreira, M.S. / Aguiar, A.C.C. / Souza, G.E. / Wenlock, M. / Jones, B. / Steinbrecher, T. / Day, T. / McPhail, J. / Burke, J. / Yeo, T. / Mok, S. / Uhlemann, A.C. / Fidock, D.A. / Chen, P. / Grodsky, N. / Deng, Y.L. / Guido, R.V.C. / Campbell, S.F. / Willis, P.A. / Dias, L.C.
History
DepositionApr 28, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,0002
Polymers112,6201
Non-polymers3801
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.849, 134.794, 141.950
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 / PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / ...PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / PtdIns-3-kinase subunit p110-alpha / p110alpha / Phosphoinositide 3-kinase alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 112619.867 Da / Num. of mol.: 1 / Fragment: UNP residues 105-1048
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: unidentified baculovirus
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-ZHY / 4-[6-(3,4,5-trimethoxyanilino)pyrazin-2-yl]benzamide


Mass: 380.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N4O4 / Feature type: SUBJECT OF INVESTIGATION
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: 2.5 Å3/Da / Density % sol: 50.79 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 8% (w/v) PEG 6000, 0.1 M CHES pH 9.75, 0.64 M Sodium Formate and AMP, 5 mM TCEP pH 7

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Data collection

DiffractionMean temperature: 95.15 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 1, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.91→141.95 Å / Num. obs: 25366 / % possible obs: 99.6 % / Redundancy: 6.5 % / Biso Wilson estimate: 106.31 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.03 / Rrim(I) all: 0.075 / Net I/σ(I): 15.9
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs
2.913-2.9236.30.97517582770.7890.4141.0622.1
13.518-141.954.90.03715563150.9980.0170.04231.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
BUSTERrefinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4TUU

4tuu


Resolution: 2.91→97.75 Å / Cor.coef. Fo:Fc: 0.9077 / Cor.coef. Fo:Fc free: 0.8981 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.371
RfactorNum. reflection% reflectionSelection details
Rfree0.2422 1281 5.06 %RANDOM
Rwork0.2054 24090 --
obs0.2074 25315 99.1 %-
Displacement parametersBiso max: 222.44 Å2 / Biso mean: 105.29 Å2 / Biso min: 44.54 Å2
Baniso -1Baniso -2Baniso -3
1-21.76 Å20 Å20 Å2
2--19.0124 Å20 Å2
3----40.7724 Å2
Refine analyzeLuzzati coordinate error obs: 0.499 Å
Refinement stepCycle: final / Resolution: 2.91→97.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7235 0 28 0 7263
Biso mean--87.38 --
Num. residues----888
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetRestraint functionWeight
X-RAY DIFFRACTIONc_mcbond_it1.3671.5SINUSOIDAL2
X-RAY DIFFRACTIONc_scbond_it1.6312HARMONIC2
X-RAY DIFFRACTIONc_mcangle_it2.4492HARMONIC5
X-RAY DIFFRACTIONc_scangle_it2.6922.5HARMONIC20
LS refinement shellResolution: 2.91→3.03 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2912 134 4.9 %
Rwork0.2562 2600 -
all0.2579 2734 -
obs--99.1 %
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5api.param

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