[English] 日本語
Yorodumi
- PDB-4gb9: Potent and Highly Selective Benzimidazole Inhibitors of PI3K-delta -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4gb9
TitlePotent and Highly Selective Benzimidazole Inhibitors of PI3K-delta
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Keywordstransferase/transferase inhibitor / kinase p110 gamma-isoform / kinase / lipid kinase / transferase-transferase inhibitor complex
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / positive regulation of endothelial cell migration / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / inflammatory response / immune response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0WR / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.438 Å
AuthorsMurray, J.M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Potent and highly selective benzimidazole inhibitors of PI3-kinase delta.
Authors: Murray, J.M. / Sweeney, Z.K. / Chan, B.K. / Balazs, M. / Bradley, E. / Castanedo, G. / Chabot, C. / Chantry, D. / Flagella, M. / Goldstein, D.M. / Kondru, R. / Lesnick, J. / Li, J. / Lucas, ...Authors: Murray, J.M. / Sweeney, Z.K. / Chan, B.K. / Balazs, M. / Bradley, E. / Castanedo, G. / Chabot, C. / Chantry, D. / Flagella, M. / Goldstein, D.M. / Kondru, R. / Lesnick, J. / Li, J. / Lucas, M.C. / Nonomiya, J. / Pang, J. / Price, S. / Salphati, L. / Safina, B. / Savy, P.P. / Seward, E.M. / Ultsch, M. / Sutherlin, D.P.
History
DepositionJul 26, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 22, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)111,2612
Polymers110,7271
Non-polymers5341
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)139.350, 66.020, 102.280
Angle α, β, γ (deg.)90.000, 98.000, 90.000
Int Tables number5
Space group name H-MC121

-
Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / ...PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 110727.102 Da / Num. of mol.: 1 / Fragment: unp residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0WR / 2-[1-({2-[2-(dimethylamino)-1H-benzimidazol-1-yl]-9-methyl-6-(morpholin-4-yl)-9H-purin-8-yl}methyl)piperidin-4-yl]propan-2-ol


Mass: 533.668 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H39N9O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.1 Å3/Da / Density % sol: 41.53 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl, pH 8.5, vapor diffusion, hanging drop, temperature 289K

-
Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 26, 2009
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→60.93 Å / Num. all: 33625 / Num. obs: 33598 / % possible obs: 97.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 44 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 14.8
Reflection shellResolution: 2.43→2.44 Å / Redundancy: 3 % / Rmerge(I) obs: 0.581 / Mean I/σ(I) obs: 3 / Num. unique all: 295 / % possible all: 89.1

-
Phasing

PhasingMethod: molecular replacement

-
Processing

Software
NameVersionClassificationNB
DENZOdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.8_1066refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TL5

3tl5


Resolution: 2.438→53.654 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.31 / Cross valid method: Random / σ(F): 1.34 / Phase error: 26.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2483 1705 5.07 %
Rwork0.2034 --
obs0.2056 33598 97.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 213.9 Å2 / Biso mean: 60.0784 Å2 / Biso min: 19.04 Å2
Refinement stepCycle: LAST / Resolution: 2.438→53.654 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6801 0 39 71 6911
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0116991
X-RAY DIFFRACTIONf_angle_d1.7429464
X-RAY DIFFRACTIONf_chiral_restr0.0971059
X-RAY DIFFRACTIONf_plane_restr0.0131197
X-RAY DIFFRACTIONf_dihedral_angle_d16.6292611
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4385-2.51020.35411320.26132469260191
2.5102-2.59120.30391600.24982682284299
2.5912-2.68380.29731330.251727112844100
2.6838-2.79130.29851460.244127072853100
2.7913-2.91830.30671590.246726912850100
2.9183-3.07220.2951390.236527292868100
3.0722-3.26460.25271510.22272693284499
3.2646-3.51660.2791290.20312704283398
3.5166-3.87050.25421330.18492665279897
3.8705-4.43030.20981470.17582585273295
4.4303-5.58080.18591370.1772589272693
5.5808-53.66730.23041390.19182668280794
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)
13.6887-0.0805-0.73991.67770.17163.50160.06-0.2596-0.33650.1946-0.03970.40930.2461-0.73140.04080.3861-0.0522-0.02360.35390.08390.471313.5358-33.700225.9742
24.36610.89820.41761.6634-0.67853.42550.0522-0.19440.0744-0.0694-0.13210.0161-0.05250.50070.09560.31850.04090.01210.3585-0.05540.248957.1367-23.017711.6934
32.4232-0.2771.65420.5564-0.54551.39430.0643-0.4364-0.23030.0894-0.0027-0.05630.1462-0.0272-0.05370.33170.04660.00380.36260.00530.30543.1998-30.525330.517
43.7989-2.41420.96546.5651-2.25823.8386-0.00080.41290.2229-0.585-0.02950.0673-0.3471-0.22920.01660.3751-0.0069-0.03930.42320.0110.3614.9097-13.49227.1837
53.186-0.97362.15142.881403.75020.001-0.11080.06820.1140.140.1623-0.061-0.2085-0.09890.34280.08170.0370.28970.0120.406419.6191-15.160624.2516
64.4401-1.38830.13182.707-0.64532.892-0.1123-0.26080.43420.36830.2350.1097-0.5417-0.3185-0.12240.40720.07650.00230.3707-0.03410.297720.9904-1.547635.0791
74.4578-2.31321.89715.804-2.81884.309-0.1311-0.07470.68540.1604-0.0538-0.8174-0.49380.42510.15150.4717-0.0625-0.03310.3801-0.0570.430235.5103-0.714836.6884
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 143 through 316 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 317 through 514 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 515 through 725 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 726 through 815 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 816 through 884 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 885 through 1038 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 1039 through 1091 )A0

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more