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- PDB-6tpe: Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 6tpe
TitleFragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE / JANUS KINASE / INHIBITOR / COMPLEX / PROTEROS BIOSTRUCTURES GMBH
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / type III interferon-mediated signaling pathway / 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 / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / type III interferon-mediated signaling pathway / 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 signaling / type I interferon-mediated signaling pathway / interleukin-6-mediated signaling pathway / 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 / 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 / response to antibiotic / protein phosphorylation / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-NTW / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.87 Å
AuthorsHansen, B.B. / Jepsen, T.H. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. ...Hansen, B.B. / Jepsen, T.H. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. / Molck, C. / Rai, S. / Nasipireddy, V.R. / Jestel, A. / Lammens, A. / Ritzen, A.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.
Authors: Hansen, B.B. / Jepsen, T.H. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. / Molck, C. / Lovato, P. / Rai, S. / Nasipireddy, V.R. / Ritzen, A.
History
DepositionDec 13, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)67,7774
Polymers67,2372
Non-polymers5412
Water0
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8892
Polymers33,6181
Non-polymers2701
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8892
Polymers33,6181
Non-polymers2701
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.423, 169.558, 43.245
Angle α, β, γ (deg.)90.000, 90.540, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A864 - 1153
2010B864 - 1153

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Components

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


Mass: 33618.328 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
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-NTW / 2-[4-(3-methyl-6-oxidanylidene-1,7-dihydropyrazolo[3,4-b]pyridin-4-yl)cyclohexyl]ethanenitrile


Mass: 270.330 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H18N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.38 Å3/Da / Density % sol: 48.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: NULL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99981 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99981 Å / Relative weight: 1
ReflectionResolution: 2.87→84.78 Å / Num. obs: 13162 / % possible obs: 96.4 % / Redundancy: 2.2 % / Biso Wilson estimate: 77.791 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.061 / Χ2: 0.976 / Net I/σ(I): 13.7 / Num. measured all: 28913
Reflection shellResolution: 2.89→3.14 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.437 / Mean I/σ(I) obs: 2.08 / Num. possible: 60 / Num. unique obs: 2874 / CC1/2: 0.724 / Rrim(I) all: 0.569 / % possible all: 96.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.87→84.78 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.875 / SU B: 61.336 / SU ML: 0.514 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.509
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2981 572 4.3 %RANDOM
Rwork0.2466 ---
obs0.2488 12870 96.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 167.17 Å2 / Biso mean: 91.506 Å2 / Biso min: 43.12 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å20 Å2-3.72 Å2
2--1.9 Å20 Å2
3----1.92 Å2
Refinement stepCycle: final / Resolution: 2.87→84.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4606 0 36 0 4642
Biso mean--70.03 --
Num. residues----566
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194427
X-RAY DIFFRACTIONr_bond_other_d0.0020.024084
X-RAY DIFFRACTIONr_angle_refined_deg1.1241.9886022
X-RAY DIFFRACTIONr_angle_other_deg0.9439305
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1865560
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.5623.864176
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.97915677
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.881523
X-RAY DIFFRACTIONr_chiral_restr0.0550.2671
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215033
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02998
Refine LS restraints NCS

Ens-ID: 1 / Number: 15312 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.06 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.87→2.944 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 43 -
Rwork0.377 892 -
all-935 -
obs--95.12 %
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)
15.0038-0.2646-0.46543.704-1.51228.76980.02750.7458-0.4326-0.45520.05640.56640.9553-0.2049-0.08380.3459-0.18790.15420.2841-0.17110.3992-2.88257.22-2.007
24.3506-0.30150.48984.5427-0.58472.87250.1972-0.2041-0.66111.06970.0033-0.21590.25310.1434-0.20040.653-0.18830.19720.1591-0.13240.446213.05150.21516.352
34.0074-0.77950.39981.24322.11948.41360.03690.62320.6302-0.5861-0.0048-0.5645-0.89830.2738-0.0320.516-0.25750.11290.31890.23510.607724.2543.35-2.194
44.2186-0.6483-0.28645.20770.39622.6398-0.0213-0.21620.70171.06360.05450.0412-0.2622-0.0104-0.03320.4875-0.1725-0.09760.16040.08510.39768.2949.81516.243
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B867 - 959
2X-RAY DIFFRACTION2B961 - 2000
3X-RAY DIFFRACTION3A867 - 959
4X-RAY DIFFRACTION4A961 - 2000

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