[English] 日本語
Yorodumi
- PDB-4d1s: Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4d1s
TitlePyrrole-3-carboxamides as potent and selective JAK2 inhibitors
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE / KINASE / JAK2 / DRUG DISCOVERY / PROTEIN KINASE INHIBITORS / STRUCTURE-ACTIVITY RELATIONSHIP / POLYCYTHEMIA VERA / TUMOUR CELL PROLIFERATION INHIBITION / ANTI-CANCER AGENTS
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex / 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 / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / Interleukin-23 signaling / positive regulation of leukocyte proliferation / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / positive regulation of epithelial cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / axon regeneration / extrinsic component of plasma membrane / response to hydroperoxide / Interleukin-20 family signaling / growth hormone receptor signaling pathway / Interleukin-6 signaling / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / positive regulation of interleukin-17 production / response to amine / signaling receptor activator activity / mesoderm development / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / response to tumor necrosis factor / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / post-translational protein modification / cellular response to dexamethasone stimulus / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / endosome lumen / positive regulation of receptor signaling pathway via JAK-STAT
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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / 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-BJG / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsBertrand, J. / Canevari, G. / Fasolini, M. / Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bindi, S. / Carenzi, D. ...Bertrand, J. / Canevari, G. / Fasolini, M. / Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bindi, S. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. / Cribioli, S. / Cristiani, C. / Della Vedova, F. / Fachin, G. / Felder, E.R. / Galvani, A. / Isacchi, A. / Mirizzi, D. / Motto, I. / Panzeri, A. / Pesenti, E. / Vianello, P. / Gnocchi, P. / Donati, D.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: Pyrrole-3-Carboxamides as Potent and Selective Jak2 Inhibitors.
Authors: Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bertrand, J. / Bindi, S. / Canevari, G. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. ...Authors: Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bertrand, J. / Bindi, S. / Canevari, G. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. / Cribioli, S. / Cristiani, C. / Della Vedova, F. / Fachin, G. / Fasolini, M. / Felder, E.R. / Galvani, A. / Isacchi, A. / Mirizzi, D. / Motto, I. / Panzeri, A. / Pesenti, E. / Vianello, P. / Gnocchi, P. / Donati, D.
History
DepositionMay 5, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2014Group: Database references
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Mar 6, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.5Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 20, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7142
Polymers35,1981
Non-polymers5161
Water2,738152
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)107.780, 69.273, 50.332
Angle α, β, γ (deg.)90.00, 99.02, 90.00
Int Tables number5
Space group name H-MC121

-
Components

#1: Protein TYROSINE-PROTEIN KINASE JAK2 / JANUS KINASE 2 / JAK-2


Mass: 35197.992 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 835-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-BJG / 2-(5-chloro-2-methylphenyl)-1-methyl-5-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1H-pyrrole-3-carboxamide


Mass: 516.037 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30ClN7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.65 Å3/Da / Density % sol: 54 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 1.5-2.2 M SODIUM MALONATE PH 7, VAPOUR DIFFUSION 293 K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jun 13, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.65→30 Å / Num. obs: 40914 / % possible obs: 92.9 % / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 23.5
Reflection shellResolution: 1.65→1.71 Å / Rmerge(I) obs: 0.14 / Mean I/σ(I) obs: 7.48 / % possible all: 63.3

-
Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2B7A

2b7a


Resolution: 1.66→25.16 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.93 / Cross valid method: THROUGHOUT / ESU R: 0.106 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23131 2089 5.1 %RANDOM
Rwork0.20351 ---
obs0.2049 38823 95.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.523 Å2
Baniso -1Baniso -2Baniso -3
1-0.56 Å20 Å20.07 Å2
2---0.28 Å20 Å2
3----0.26 Å2
Refinement stepCycle: LAST / Resolution: 1.66→25.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2346 0 37 152 2535
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.022512
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.5681.9953398
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6595298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.08423.876129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.35915473
X-RAY DIFFRACTIONr_dihedral_angle_4_deg27.7451521
X-RAY DIFFRACTIONr_chiral_restr0.170.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0211919
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.664→1.707 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.653 124 -
Rwork0.581 2522 -
obs--84.48 %

+
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