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- PDB-4c61: Inhibitors of Jak2 Kinase domain -

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Basic information

Entry
Database: PDB / ID: 4c61
TitleInhibitors of Jak2 Kinase domain
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE / KINASE
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic 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 / Signaling by Erythropoietin ...interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic 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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet activation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / cellular response to interleukin-3 / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of epithelial cell apoptotic process / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / mesoderm development / positive regulation of natural killer cell proliferation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / post-translational protein modification / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / caveola / 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 / Jak1 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 / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / SH2 domain / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
ACETATE ION / Chem-LMM / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsRead, J.A. / Green, I. / Pollard, H. / Howard, T.
Citation
Journal: J.Med.Chem. / Year: 2014
Title: Discovery of 1-Methyl-1H-Imidazole Derivatives as Potent Jak2 Inhibitors.
Authors: Su, Q. / Ioannidis, S. / Chuaqui, C. / Almeida, L. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Block, M. / Howard, T. / Huang, S. / Huszar, D. / Read, J.A. / Rivard Costa, C. / Shi, J. / ...Authors: Su, Q. / Ioannidis, S. / Chuaqui, C. / Almeida, L. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Block, M. / Howard, T. / Huang, S. / Huszar, D. / Read, J.A. / Rivard Costa, C. / Shi, J. / Su, M. / Ye, M. / Zinda, M.
#1: Journal: J.Med.Chem. / Year: 2011
Title: Discovery of 5-Chloro-N2-[(1S)-1-(5-Fluoropyrimidin-2-Yl)Ethyl]-N4-(5-Methyl-1H-Pyrazol-3-Yl)Pyrimidine-2,4-Diamine (Azd1480) as a Novel Inhibitor of the Jak/Stat Pathway.
Authors: Ioannidis, S. / Lamb, M.L. / Wang, T. / Almeida, L. / Block, M.H. / Davies, A.M. / Peng, B. / Su, M. / Zhang, H. / Hoffmann, E. / Rivard, C. / Green, I. / Howard, T. / Pollard, H. / Read, J. ...Authors: Ioannidis, S. / Lamb, M.L. / Wang, T. / Almeida, L. / Block, M.H. / Davies, A.M. / Peng, B. / Su, M. / Zhang, H. / Hoffmann, E. / Rivard, C. / Green, I. / Howard, T. / Pollard, H. / Read, J. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Ye, M. / Huszar, D. / Zinda, M.
History
DepositionSep 17, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 8, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Dec 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_conn / 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_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TYROSINE-PROTEIN KINASE JAK2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1387
Polymers70,1922
Non-polymers9465
Water3,585199
1
A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5984
Polymers35,0961
Non-polymers5033
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5393
Polymers35,0961
Non-polymers4432
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.880, 127.090, 135.210
Angle α, β, γ (deg.)90.00, 97.33, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 35095.816 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN RESIDUES 835-1132 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): STAR / References: UniProt: O60674, EC: 2.7.1.112
#2: Chemical ChemComp-LMM / N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-7-methyl-N4-(1-methylimidazol-4-yl)thieno[3,2-d]pyrimidine-2,4-diamine


Mass: 384.434 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H17FN8S
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 199 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsK943 AND K945A DOUBLE MUTANT

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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: 2.86 Å3/Da / Density % sol: 57 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Sep 4, 2008 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.45→134 Å / Num. obs: 25971 / % possible obs: 96.2 % / Observed criterion σ(I): 2 / Redundancy: 4.2 % / Biso Wilson estimate: 56.9 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 13.4
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 2.5 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XA4

2xa4


Resolution: 2.45→26.82 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.9273 / SU R Cruickshank DPI: 0.357 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.35 / SU Rfree Blow DPI: 0.223 / SU Rfree Cruickshank DPI: 0.227
RfactorNum. reflection% reflectionSelection details
Rfree0.2168 1305 5.03 %RANDOM
Rwork0.1806 ---
obs0.1824 25920 95.99 %-
Displacement parametersBiso mean: 56.69 Å2
Baniso -1Baniso -2Baniso -3
1--4.5272 Å20 Å2-0.9289 Å2
2--1.9297 Å20 Å2
3---2.5976 Å2
Refine analyzeLuzzati coordinate error obs: 0.341 Å
Refinement stepCycle: LAST / Resolution: 2.45→26.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4398 0 63 199 4660
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014556HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.126165HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1563SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes111HARMONIC2
X-RAY DIFFRACTIONt_gen_planes711HARMONIC5
X-RAY DIFFRACTIONt_it4556HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.12
X-RAY DIFFRACTIONt_other_torsion19.77
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion571SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5260SEMIHARMONIC4
LS refinement shellResolution: 2.45→2.55 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2498 136 4.7 %
Rwork0.2118 2759 -
all0.2137 2895 -
obs--95.99 %
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)
10.8077-0.13740.08043.68331.34323.22160.0723-0.10390.01840.3134-0.47310.3597-0.0699-0.47140.4008-0.12670.03330.0695-0.0547-0.0861-0.12317.615413.337745.5201
21.98110.0456-0.99991.0098-0.41062.2355-0.2897-0.1444-0.18130.11260.0255-0.1570.40730.31120.2642-0.04820.11590.0021-0.0705-0.0091-0.0914-9.8631-12.559120.9988
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B

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