[English] 日本語
Yorodumi
- PDB-4f08: Discovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4f08
TitleDiscovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / JAK2 / kinase domain / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / type 1 angiotensin receptor binding / post-embryonic hemopoiesis / interleukin-12 receptor complex / erythropoietin-mediated signaling pathway / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of MHC class II biosynthetic process / positive regulation of NK T cell proliferation / acetylcholine receptor binding / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / regulation of nitric oxide biosynthetic process / growth hormone receptor binding / positive regulation of cell-substrate adhesion / axon regeneration / response to hydroperoxide / extrinsic component of cytoplasmic side of plasma membrane / regulation of receptor signaling pathway via JAK-STAT / negative regulation of cardiac muscle cell apoptotic process / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of tyrosine phosphorylation of STAT protein / negative regulation of cell-cell adhesion / extrinsic component of plasma membrane / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / peptide hormone receptor binding / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / response to amine / Prolactin receptor signaling / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / mesoderm development / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / response to tumor necrosis factor / signaling receptor activator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cellular response to dexamethasone stimulus / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Growth hormone receptor signaling / Erythropoietin activates RAS / phosphatidylinositol 3-kinase binding / Signaling by CSF3 (G-CSF) / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response / SH2 domain binding / post-translational protein modification / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / endosome lumen / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-1RS / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.82 Å
AuthorsMurray, J.M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery and Optimization of C-2 Methyl Imidazopyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2.
Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, ...Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, S. / Hamman, C. / Hanan, E.J. / Harstad, E. / Hewitt, P.R. / Hurley, C.A. / Jin, T. / Johnson, A. / Johnson, T. / Kenny, J.R. / Koehler, M.F. / Bir Kohli, P. / Kulagowski, J.J. / Labadie, S. / Liao, J. / Liimatta, M. / Lin, Z. / Lupardus, P.J. / Maxey, R.J. / Murray, J.M. / Pulk, R. / Rodriguez, M. / Savage, S. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S.I. / Xiao, L. / Xiao, Y.
History
DepositionMay 3, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 4, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 25, 2012Group: Database references
Revision 1.2May 29, 2013Group: Non-polymer description
Revision 1.3Sep 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_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

-
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)71,4554
Polymers70,9732
Non-polymers4832
Water00
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7282
Polymers35,4861
Non-polymers2411
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7282
Polymers35,4861
Non-polymers2411
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)110.923, 110.923, 70.732
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

-
Components

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


Mass: 35486.254 Da / Num. of mol.: 2 / Fragment: UNP residues 833-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2, JAK2 kinase domain / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-1RS / 1-(piperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine


Mass: 241.292 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H15N5
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 3.17 Å3/Da / Density % sol: 61.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.2 M ammonium acetate, 0.1M sodium citrate pH6, 25% PEG 8000, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 16, 2010
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.82→50 Å / Num. obs: 20873 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5 % / Biso Wilson estimate: 55 Å2 / Rmerge(I) obs: 0.102 / Χ2: 1.055 / Net I/σ(I): 9.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.82-2.924.40.51820451.045198.3
2.92-3.044.90.43820521.077199.9
3.04-3.185.10.35220881.0531100
3.18-3.345.10.24320671.0731100
3.34-3.555.10.16420841.0811100
3.55-3.835.10.1120951.0431100
3.83-4.215.10.07820701.0371100
4.21-4.825.10.07621041.0791100
4.82-6.0750.08221011.0441100
6.07-504.90.03421671.0141100

-
Phasing

PhasingMethod: molecular replacement

-
Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2B7A

2b7a


Resolution: 2.82→49.61 Å / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 1.024 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.241 1034 4.96 %RANDOM
Rwork0.2131 ---
obs0.2145 20852 99.63 %-
Displacement parametersBiso max: 182.23 Å2 / Biso mean: 58.8535 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--0.5167 Å20 Å20 Å2
2---0.5167 Å20 Å2
3---1.0334 Å2
Refine analyzeLuzzati coordinate error obs: 0.399 Å
Refinement stepCycle: LAST / Resolution: 2.82→49.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4768 0 36 0 4804
LS refinement shellResolution: 2.82→2.97 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2751 152 5.13 %
Rwork0.2468 2809 -
all0.2483 2961 -
obs--99.63 %

+
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