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- PDB-8vof: GI targeted CpPI4K inhibitor -

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Basic information

Entry
Database: PDB / ID: 8vof
TitleGI targeted CpPI4K inhibitor
Components
  • Isoform 2 of Phosphatidylinositol 4-kinase beta,Isoform 2 of Phosphatidylinositol 4-kinase beta,Phosphatidylinositol 4-kinase beta
  • Ras-related protein Rab-11A
KeywordsTRANSFERASE / Inhibitor complex / chimera / Cryptosporidiosis
Function / homology
Function and homology information


: / regulation of protein localization to centrosome / synaptic vesicle endosomal processing / : / regulation of endocytic recycling / 1-phosphatidylinositol 4-kinase / 1-phosphatidylinositol 4-kinase activity / establishment of protein localization to organelle / postsynaptic recycling endosome / positive regulation of mitotic cytokinetic process ...: / regulation of protein localization to centrosome / synaptic vesicle endosomal processing / : / regulation of endocytic recycling / 1-phosphatidylinositol 4-kinase / 1-phosphatidylinositol 4-kinase activity / establishment of protein localization to organelle / postsynaptic recycling endosome / positive regulation of mitotic cytokinetic process / establishment of vesicle localization / rough endoplasmic reticulum membrane / regulation of protein transport / regulation of cilium assembly / amyloid-beta clearance by transcytosis / vesicle-mediated transport in synapse / neurotransmitter receptor transport, endosome to postsynaptic membrane / exosomal secretion / presynaptic endosome / VxPx cargo-targeting to cilium / plasma membrane to endosome transport / regulation of vesicle-mediated transport / protein transmembrane transport / Synthesis of PIPs at the Golgi membrane / astral microtubule organization / RAB geranylgeranylation / myosin V binding / multivesicular body assembly / phosphatidylinositol biosynthetic process / melanosome transport / protein localization to cilium / Golgi to plasma membrane protein transport / establishment of protein localization to membrane / TBC/RABGAPs / protein localization to cell surface / syntaxin binding / dynein light intermediate chain binding / mitotic metaphase chromosome alignment / lysosome organization / phosphatidylinositol phosphate biosynthetic process / inner ear development / phosphatidylinositol-mediated signaling / exocytosis / cleavage furrow / positive regulation of epithelial cell migration / mitotic spindle assembly / positive regulation of G2/M transition of mitotic cell cycle / transport vesicle / phagocytic vesicle / multivesicular body / vesicle-mediated transport / 14-3-3 protein binding / Anchoring of the basal body to the plasma membrane / receptor-mediated endocytosis / cytoplasmic vesicle membrane / trans-Golgi network membrane / regulation of cytokinesis / small monomeric GTPase / protein localization to plasma membrane / positive regulation of protein localization to plasma membrane / Translocation of SLC2A4 (GLUT4) to the plasma membrane / centriole / trans-Golgi network / recycling endosome / regulation of long-term neuronal synaptic plasticity / Schaffer collateral - CA1 synapse / recycling endosome membrane / spindle pole / neuron projection development / endocytic vesicle membrane / Vasopressin regulates renal water homeostasis via Aquaporins / synaptic vesicle membrane / G protein activity / cytoplasmic vesicle / microtubule binding / vesicle / mitochondrial outer membrane / endosome / Golgi membrane / GTPase activity / centrosome / GTP binding / perinuclear region of cytoplasm / glutamatergic synapse / Golgi apparatus / signal transduction / protein-containing complex / extracellular exosome / ATP binding / membrane / cytoplasm / cytosol
Similarity search - Function
: / : / PI4KB/PIK1, accessory (PIK) domain / : / Small GTPase Rab domain profile. / 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 ...: / : / PI4KB/PIK1, accessory (PIK) domain / : / Small GTPase Rab domain profile. / 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 / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / GUANOSINE-5'-DIPHOSPHATE / Ras-related protein Rab-11A / Phosphatidylinositol 4-kinase beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsKnapp, M.S. / Cuellar, C. / Mamo, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Microbiol / Year: 2024
Title: Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis.
Authors: Manjunatha, U.H. / Lakshminarayana, S.B. / Jumani, R.S. / Chao, A.T. / Young, J.M. / Gable, J.E. / Knapp, M. / Hanna, I. / Galarneau, J.R. / Cantwell, J. / Kulkarni, U. / Turner, M. / Lu, P. ...Authors: Manjunatha, U.H. / Lakshminarayana, S.B. / Jumani, R.S. / Chao, A.T. / Young, J.M. / Gable, J.E. / Knapp, M. / Hanna, I. / Galarneau, J.R. / Cantwell, J. / Kulkarni, U. / Turner, M. / Lu, P. / Darrell, K.H. / Watson, L.C. / Chan, K. / Patra, D. / Mamo, M. / Luu, C. / Cuellar, C. / Shaul, J. / Xiao, L. / Chen, Y.B. / Carney, S.K. / Lakshman, J. / Osborne, C.S. / Zambriski, J.A. / Aziz, N. / Sarko, C. / Diagana, T.T.
History
DepositionJan 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _citation.year
Revision 1.2Oct 30, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _pdbx_entry_details.has_protein_modification
Revision 1.3Nov 13, 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: Isoform 2 of Phosphatidylinositol 4-kinase beta,Isoform 2 of Phosphatidylinositol 4-kinase beta,Phosphatidylinositol 4-kinase beta
B: Ras-related protein Rab-11A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,2265
Polymers85,2092
Non-polymers1,0163
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3180 Å2
ΔGint-29 kcal/mol
Surface area28450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.570, 105.224, 186.423
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Isoform 2 of Phosphatidylinositol 4-kinase beta,Isoform 2 of Phosphatidylinositol 4-kinase beta,Phosphatidylinositol 4-kinase beta / PI4K-beta / PI4Kbeta / PtdIns 4-kinase beta / NPIK / PI4K92 / PI4KIII


Mass: 60799.918 Da / Num. of mol.: 1 / Mutation: L294A,L374Y,P597Y
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PI4KB, PIK4CB / Production host: unidentified baculovirus
References: UniProt: Q9UBF8, 1-phosphatidylinositol 4-kinase
#2: Protein Ras-related protein Rab-11A / Rab-11 / YL8


Mass: 24409.547 Da / Num. of mol.: 1 / Mutation: Q70L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAB11A, RAB11 / Production host: unidentified baculovirus / References: UniProt: P62491, small monomeric GTPase

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Non-polymers , 4 types, 9 molecules

#3: Chemical ChemComp-A1ADE / methyl 2-chloro-5-(methyl{(8R)-3-[4-(methylcarbamoyl)phenyl]pyrazolo[1,5-a]pyridine-5-carbonyl}amino)benzoate


Mass: 476.912 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H21ClN4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.8 Å3/Da / Density % sol: 56 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.5M ammonium sulfate, 0.088M sodium citrate, 0.875M lithium sulfate, 2.4% glycerol, 2.5% ethylene glycol, 50mM HEPES pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→53.51 Å / Num. obs: 19983 / % possible obs: 99.8 % / Redundancy: 6.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.116 / Rpim(I) all: 0.049 / Rrim(I) all: 0.126 / Χ2: 0.82 / Net I/σ(I): 10.1 / Num. measured all: 130663
Reflection shellResolution: 3→3.16 Å / % possible obs: 99.1 % / Redundancy: 6.4 % / Rmerge(I) obs: 1.431 / Num. measured all: 18106 / Num. unique obs: 2818 / CC1/2: 0.875 / Rpim(I) all: 0.608 / Rrim(I) all: 1.557 / Χ2: 0.68 / Net I/σ(I) obs: 1.2

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→50.63 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.27 958 4.86 %Random
Rwork0.2252 ---
obs0.2274 19722 98.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→50.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4874 0 67 6 4947
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025039
X-RAY DIFFRACTIONf_angle_d0.4756866
X-RAY DIFFRACTIONf_dihedral_angle_d12.2391734
X-RAY DIFFRACTIONf_chiral_restr0.04796
X-RAY DIFFRACTIONf_plane_restr0.003869
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.160.43011380.38662537X-RAY DIFFRACTION97
3.16-3.350.36081210.32812630X-RAY DIFFRACTION99
3.35-3.610.31991330.26312646X-RAY DIFFRACTION99
3.61-3.980.30951510.21312648X-RAY DIFFRACTION99
3.98-4.550.24541370.18852674X-RAY DIFFRACTION99
4.55-5.730.25031480.20932727X-RAY DIFFRACTION100
5.73-50.630.22231300.20522902X-RAY DIFFRACTION100
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)
12.4109-0.3119-0.97822.62521.43248.0061-0.08390.36820.1304-0.15510.1284-0.04480.1742-0.02460.03241.4054-0.14080.0340.59680.01690.5682-18.7477-7.63688.6038
24.5290.0423-2.45383.34651.06123.69890.1451-0.35770.15650.0864-0.15170.2965-0.6392-0.1936-0.00021.6554-0.01820.01580.7955-0.220.666-29.6394-0.876239.5075
31.63330.1159-0.03713.64030.72612.6173-0.1372-0.5363-0.18280.50630.0345-0.00660.32780.35050.12941.32030.08860.0470.68570.03610.5065-19.3045-27.120230.1063
41.5903-0.1280.37982.28630.14738.1546-0.12290.6272-0.1943-0.901-0.00020.2219-0.8189-0.2220.29211.675-0.27030.09531.29890.20720.9583-14.6181-2.3072-34.0297
50.0466-0.5452-0.45824.19613.02342.25480.14021.3934-0.0072-1.1363-0.1481-1.05580.2012-0.25280.12961.8239-0.2183-0.0071.3165-0.02680.7134-14.999-6.9201-18.1653
61.5907-1.2713-0.43591.0810.36410.2637-0.39081.8628-0.75170.56660.88160.92880.88660.0878-0.061.7602-0.23880.1231.23280.0860.8963-12.2508-13.5567-15.9257
74.5405-1.2888-0.17923.29391.71282.81840.36131.58480.518-0.809-0.05260.29880.3539-0.8990.12131.5789-0.123-0.04171.51790.33510.6954-16.174-6.9726-32.1054
81.3129-1.2637-0.32411.88871.06481.12690.6683-0.19821.0214-1.54271.2019-1.5219-0.59760.3719-0.36551.5137-0.04850.19921.2450.06391.0867-2.42260.7684-25.9892
91.722-0.461-0.34824.4627-1.49695.5039-0.2352-0.00120.81450.48710.2134-0.5112-1.3476-0.481-0.34781.8328-0.10160.08270.89170.27640.8824-16.92265.9202-15.2108
103.0272-0.7562-0.17610.31651.04297.73220.28030.66660.4950.20630.00390.0766-0.6082-2.4954-0.57331.1342-0.08330.05161.71530.43730.776-24.3234-1.6947-17.1355
112.66541.0147-2.02613.0748-2.83632.9743-0.12620.8970.6791-0.99790.90331.1869-0.9265-1.7725-0.65341.1119-0.106-0.05361.55420.20310.6587-23.33161.592-32.2659
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 127 through 307 )
2X-RAY DIFFRACTION2chain 'A' and (resid 308 through 540 )
3X-RAY DIFFRACTION3chain 'A' and (resid 541 through 782 )
4X-RAY DIFFRACTION4chain 'B' and (resid 8 through 17 )
5X-RAY DIFFRACTION5chain 'B' and (resid 18 through 32 )
6X-RAY DIFFRACTION6chain 'B' and (resid 33 through 45 )
7X-RAY DIFFRACTION7chain 'B' and (resid 46 through 67 )
8X-RAY DIFFRACTION8chain 'B' and (resid 68 through 85 )
9X-RAY DIFFRACTION9chain 'B' and (resid 86 through 146 )
10X-RAY DIFFRACTION10chain 'B' and (resid 147 through 160 )
11X-RAY DIFFRACTION11chain 'B' and (resid 161 through 179 )

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