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- PDB-4fk6: JAK1 kinase (JH1 domain) in complex with compound 72 -

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Basic information

Entry
Database: PDB / ID: 4fk6
TitleJAK1 kinase (JH1 domain) in complex with compound 72
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / phospho transfer / phospho tyrosine / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway ...protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-2 signaling / growth hormone receptor binding / Other interleukin signaling / IFNG signaling activates MAPKs / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / type I interferon-mediated signaling pathway / Interleukin-6 signaling / positive regulation of sprouting angiogenesis / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / Evasion by RSV of host interferon responses / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / ISG15 antiviral mechanism / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / 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 / 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 ...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 / 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 / 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
Chem-0UJ / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsEigenbrot, C. / Steffek, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.
Authors: Labadie, S. / Dragovich, P.S. / Barrett, K. / Blair, W.S. / Bergeron, P. / Chang, C. / Deshmukh, G. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Hurley, C.A. / Johnson, A. / Kenny, J.R. / ...Authors: Labadie, S. / Dragovich, P.S. / Barrett, K. / Blair, W.S. / Bergeron, P. / Chang, C. / Deshmukh, G. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Hurley, C.A. / Johnson, A. / Kenny, J.R. / Kohli, P.B. / Kulagowski, J.J. / Liimatta, M. / Lupardus, P.J. / Mendonca, R. / Murray, J.M. / Pulk, R. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S. / Zak, M.
History
DepositionJun 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 7, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Database references
Revision 1.2Sep 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 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)70,2124
Polymers69,4932
Non-polymers7192
Water2,486138
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1062
Polymers34,7471
Non-polymers3591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1062
Polymers34,7471
Non-polymers3591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.248, 169.966, 43.805
Angle α, β, γ (deg.)90.00, 90.51, 90.00
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: JH1 (kinase) 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-0UJ / N-({1-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl}methyl)methanesulfonamide


Mass: 359.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21N5O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 46.91 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: MES/PEG6000, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 1, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 31343 / Num. obs: 31252 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -2 / Redundancy: 3.4 % / Biso Wilson estimate: 44.66 Å2 / Rsym value: 0.08 / Net I/σ(I): 14

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
BUSTER2.11.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B7A

2b7a


Resolution: 2.2→43.25 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.9086 / SU R Cruickshank DPI: 0.299 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -2 / Stereochemistry target values: Engh & Huber / Details: TLS applied using 4 groups
RfactorNum. reflection% reflectionSelection details
Rfree0.2512 1490 4.77 %RANDOM
Rwork0.2094 ---
all0.2113 31343 --
obs0.2113 31252 97.8 %-
Displacement parametersBiso mean: 54.54 Å2
Baniso -1Baniso -2Baniso -3
1--4.9771 Å20 Å22.3573 Å2
2--10.5914 Å20 Å2
3----5.6143 Å2
Refine analyzeLuzzati coordinate error obs: 0.352 Å
Refinement stepCycle: LAST / Resolution: 2.2→43.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4663 0 50 138 4851
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094858HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.056565HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1723SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes129HARMONIC2
X-RAY DIFFRACTIONt_gen_planes679HARMONIC5
X-RAY DIFFRACTIONt_it4858HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion18.45
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion599SEMIHARMONIC5
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_contact5448SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.27 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2284 122 5.03 %
Rwork0.2343 2304 -
all0.234 2426 -
obs--97.8 %
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)
11.155-0.57930.69943.2615-1.02824.2499-0.00430.0877-0.1441-0.54910.03930.53940.0969-0.2396-0.035-0.0407-0.0055-0.0897-0.00880.0040.0859-4.928658.2786-2.2774
21.954-0.10080.25683.9066-0.77221.4106-0.0659-0.0898-0.14860.54830.049-0.4495-0.01960.08750.01690.063-0.0111-0.0735-0.1010.0068-0.023312.339651.338116.8743
31.7484-0.0518-0.28213.65130.98314.0917-0.00980.19480.1526-0.53940.0836-0.5491-0.11050.1886-0.0739-0.13380.02380.0722-0.0047-0.00380.045725.85553.8943-1.7435
41.9873-0.1365-0.18724.10650.89171.6495-0.1034-0.10760.15120.54090.07430.3813-0.0158-0.10240.0291-0.02740.0160.046-0.074-0.0041-0.06419.094610.255916.9032
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|863 - 959}A863 - 959
2X-RAY DIFFRACTION2{A|960 - 1154}A960 - 1154
3X-RAY DIFFRACTION3{B|864 - 959}B864 - 959
4X-RAY DIFFRACTION4{B|960 - 1154}B960 - 1154

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