[English] 日本語
Yorodumi
- PDB-8bx9: Crystal structure of JAK2 JH1 in complex with ilginatinib -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8bx9
TitleCrystal structure of JAK2 JH1 in complex with ilginatinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Janus kinase / inhibitor complex / JAK2 / JH1
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / response to interleukin-12 / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / positive regulation of signaling receptor activity / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK3 (ERK1) activation / Prolactin receptor signaling / negative regulation of DNA binding / response to amine / : / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-17 production / mesoderm development / MAPK1 (ERK2) activation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / type II interferon-mediated signaling pathway / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / Signaling by CSF3 (G-CSF) / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / endosome lumen / positive regulation of cell differentiation
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / SH2 domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Ilginatinib / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsHaikarainen, T.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland Finland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.
Authors: Miao, Y. / Virtanen, A. / Zmajkovic, J. / Hilpert, M. / Skoda, R.C. / Silvennoinen, O. / Haikarainen, T.
History
DepositionDec 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4726
Polymers74,5372
Non-polymers9354
Water8,665481
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7363
Polymers37,2681
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7363
Polymers37,2681
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.526, 68.883, 107.956
Angle α, β, γ (deg.)90.000, 99.130, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2

-
Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 37268.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: PTR is phosphorylated tyrosine residue. / Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-S59 / Ilginatinib / ~{N}6-[(1~{S})-1-(4-fluorophenyl)ethyl]-4-(1-methylpyrazol-4-yl)-~{N}2-pyrazin-2-yl-pyridine-2,6-diamine


Mass: 389.429 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20FN7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 481 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.81 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.2 / Details: 0.1 M Gly-Gly pH 8.2, 1.6 M Na-malonate

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 29, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.4→78.74 Å / Num. obs: 141301 / % possible obs: 99.7 % / Redundancy: 6.9 % / Biso Wilson estimate: 14.37 Å2 / CC1/2: 1 / Net I/σ(I): 9.8
Reflection shellResolution: 1.4→1.42 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 6815 / CC1/2: 0.809 / % possible all: 97.4

-
Processing

Software
NameVersionClassification
GDAdata collection
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VN8

6vn8


Resolution: 1.4→67.14 Å / SU ML: 0.1493 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.6472
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2228 7069 5.01 %
Rwork0.1913 133929 -
obs0.1929 140998 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.56 Å2
Refinement stepCycle: LAST / Resolution: 1.4→67.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4908 0 66 481 5455
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01175214
X-RAY DIFFRACTIONf_angle_d1.08597076
X-RAY DIFFRACTIONf_chiral_restr0.0827747
X-RAY DIFFRACTIONf_plane_restr0.0138916
X-RAY DIFFRACTIONf_dihedral_angle_d13.46522016
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.35342220.31894312X-RAY DIFFRACTION96.43
1.42-1.430.32452320.294427X-RAY DIFFRACTION99.25
1.43-1.450.31022400.26974407X-RAY DIFFRACTION99.4
1.45-1.470.32172240.25514447X-RAY DIFFRACTION99.17
1.47-1.490.30842350.25164487X-RAY DIFFRACTION99.75
1.49-1.510.2852600.24154380X-RAY DIFFRACTION99.34
1.51-1.530.27122360.23784467X-RAY DIFFRACTION99.56
1.53-1.550.27612110.22834444X-RAY DIFFRACTION99.66
1.55-1.580.28832530.22624470X-RAY DIFFRACTION99.58
1.58-1.60.24812050.22274484X-RAY DIFFRACTION99.55
1.6-1.630.27752290.21994451X-RAY DIFFRACTION99.77
1.63-1.660.24852480.20844445X-RAY DIFFRACTION99.55
1.66-1.690.22582440.20694461X-RAY DIFFRACTION99.75
1.69-1.730.22982270.19944473X-RAY DIFFRACTION99.81
1.73-1.760.25482430.194458X-RAY DIFFRACTION100
1.76-1.80.22342460.19484489X-RAY DIFFRACTION99.94
1.8-1.850.24972330.18884445X-RAY DIFFRACTION99.91
1.85-1.90.21612250.18884491X-RAY DIFFRACTION99.81
1.9-1.960.21432370.17274472X-RAY DIFFRACTION99.6
1.96-2.020.1992560.16344424X-RAY DIFFRACTION99.74
2.02-2.090.17082510.1614499X-RAY DIFFRACTION99.92
2.09-2.170.20682450.15194475X-RAY DIFFRACTION99.98
2.17-2.270.17932260.15114475X-RAY DIFFRACTION99.85
2.27-2.390.18282280.14964505X-RAY DIFFRACTION99.81
2.39-2.540.1852400.16014494X-RAY DIFFRACTION99.85
2.54-2.740.21272100.16834517X-RAY DIFFRACTION99.83
2.74-3.020.22172280.18564529X-RAY DIFFRACTION99.85
3.02-3.450.252580.18974509X-RAY DIFFRACTION99.94
3.45-4.350.17862300.18414512X-RAY DIFFRACTION99.48
4.35-67.140.23152470.21954480X-RAY DIFFRACTION97.04

+
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