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- PDB-5hx8: Jak1 complex with 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol... -

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Basic information

Entry
Database: PDB / ID: 5hx8
TitleJak1 complex with 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway ...type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / Interleukin-15 signaling / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / IFNG signaling activates MAPKs / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / MAPK1 (ERK2) activation / Interleukin-10 signaling / Regulation of IFNA/IFNB signaling / 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 / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / Interleukin-7 signaling / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / cellular response to virus / positive regulation of protein localization to nucleus / ISG15 antiviral mechanism / cytoplasmic side of plasma membrane / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / receptor complex / endosome / intracellular signal transduction / protein phosphorylation / response to antibiotic / focal adhesion / ubiquitin protein ligase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak1 / 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 ...Tyrosine-protein kinase, non-receptor Jak1 / 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 / 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-66P / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsSu, H.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Authors: Simov, V. / Deshmukh, S.V. / Dinsmore, C.J. / Elwood, F. / Fernandez, R.B. / Garcia, Y. / Gibeau, C. / Gunaydin, H. / Jung, J. / Katz, J.D. / Kraybill, B. / Lapointe, B. / Patel, S.B. / Siu, ...Authors: Simov, V. / Deshmukh, S.V. / Dinsmore, C.J. / Elwood, F. / Fernandez, R.B. / Garcia, Y. / Gibeau, C. / Gunaydin, H. / Jung, J. / Katz, J.D. / Kraybill, B. / Lapointe, B. / Patel, S.B. / Siu, T. / Su, H. / Young, J.R.
History
DepositionJan 29, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK1
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,1404
Polymers69,4932
Non-polymers6472
Water2,648147
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0702
Polymers34,7471
Non-polymers3231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0702
Polymers34,7471
Non-polymers3231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.760, 172.970, 44.720
Angle α, β, γ (deg.)90.000, 93.600, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase JAK1 / Janus kinase 1 / JAK-1


Mass: 34746.594 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 854-1154
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-66P / 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one / 4-[(cis-4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)pyridin-2(1H)-one


Mass: 323.392 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H21N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.39 Å3/Da / Density % sol: 48.47 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 100mM MES pH 6.25, 33 % PEG 6000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 28, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→44.63 Å / Num. obs: 32260 / % possible obs: 98.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 46.44 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.039 / Rrim(I) all: 0.072 / Net I/σ(I): 12.6 / Num. measured all: 108761
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.463.40.4533075191750.8310.2910.542.898.8
4.92-44.633.20.028901828210.9970.0190.0343194.9

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Processing

Software
NameVersionClassification
Aimless0.3.6data scaling
BUSTER-TNT2.11.5refinement
PDB_EXTRACT3.2data extraction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→44.63 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.9108 / SU R Cruickshank DPI: 0.266 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.255 / SU Rfree Blow DPI: 0.199 / SU Rfree Cruickshank DPI: 0.205
RfactorNum. reflection% reflectionSelection details
Rfree0.2397 1632 5.07 %RANDOM
Rwork0.197 ---
obs0.1992 32220 98.29 %-
Displacement parametersBiso max: 151.01 Å2 / Biso mean: 49.8 Å2 / Biso min: 19.06 Å2
Baniso -1Baniso -2Baniso -3
1-1.298 Å20 Å23.3303 Å2
2--5.911 Å20 Å2
3----7.209 Å2
Refine analyzeLuzzati coordinate error obs: 0.288 Å
Refinement stepCycle: final / Resolution: 2.2→44.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4629 0 48 147 4824
Biso mean--29.97 46.1 -
Num. residues----574
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1699SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC8
X-RAY DIFFRACTIONt_gen_planes714HARMONIC8
X-RAY DIFFRACTIONt_it4789HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion595SEMIHARMONIC5
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_contact5460SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4789HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg6466HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion2.03
X-RAY DIFFRACTIONt_other_torsion18
LS refinement shellResolution: 2.2→2.27 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2648 148 4.99 %
Rwork0.2145 2818 -
all0.217 2966 -
obs--98.29 %

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