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

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Basic information

Entry
Database: PDB / ID: 6tpf
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


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 / 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-NTQ / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.31 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. / Griessner, 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
Revision 1.2Nov 13, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)67,9374
Polymers67,2372
Non-polymers7012
Water1,27971
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9692
Polymers33,6181
Non-polymers3501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9692
Polymers33,6181
Non-polymers3501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.728, 171.198, 44.330
Angle α, β, γ (deg.)90.000, 91.840, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: VAL / Beg label comp-ID: VAL / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: _ / Auth seq-ID: 865 - 1153 / Label seq-ID: 2 - 290

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-NTQ / (1~{S})-2,2-bis(fluoranyl)-~{N}-[4-(3-methyl-6-oxidanylidene-2,7-dihydropyrazolo[3,4-b]pyridin-4-yl)cyclohexyl]cyclopropane-1-carboxamide


Mass: 350.363 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H20F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.48 Å3/Da / Density % sol: 50.51 %
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: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 2.31→85.6 Å / Num. obs: 26488 / % possible obs: 95.2 % / Redundancy: 2.2 % / Biso Wilson estimate: 53.766 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.056 / Rrim(I) all: 0.074 / Χ2: 0.958 / Net I/σ(I): 10.73 / Num. measured all: 59165 / Scaling rejects: 1
Reflection shellResolution: 2.31→2.56 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.435 / Mean I/σ(I) obs: 2.26 / Num. possible: 102 / Num. unique obs: 7043 / CC1/2: 0.705 / Rrim(I) all: 0.567 / % possible all: 95.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.31→85.6 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.887 / SU B: 30.068 / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.514 / ESU R Free: 0.332
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3268 1176 4.4 %RANDOM
Rwork0.2633 ---
obs0.2661 25312 95.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 145.01 Å2 / Biso mean: 65.906 Å2 / Biso min: 21.64 Å2
Baniso -1Baniso -2Baniso -3
1-0.6 Å2-0 Å2-1.19 Å2
2--2.73 Å20 Å2
3----3.25 Å2
Refinement stepCycle: final / Resolution: 2.31→85.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4600 0 50 71 4721
Biso mean--60.17 48.51 -
Num. residues----566
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194650
X-RAY DIFFRACTIONr_bond_other_d0.0030.024390
X-RAY DIFFRACTIONr_angle_refined_deg1.7071.9976312
X-RAY DIFFRACTIONr_angle_other_deg1.299310115
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9125568
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.82524.372199
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.48415793
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0991522
X-RAY DIFFRACTIONr_chiral_restr0.090.2688
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215193
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021037
Refine LS restraints NCS

Ens-ID: 1 / Number: 16976 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.31→2.37 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.426 69 -
Rwork0.38 1873 -
all-1942 -
obs--94.69 %
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)
13.512-0.90850.78912.77860.07867.393-0.0490.48240.2496-0.55910.0758-0.2991-0.67130.6509-0.02670.1943-0.06780.09760.18210.02520.432824.5453.374-2.566
23.63420.6735-0.0333.87910.74952.7630.1234-0.21950.45870.4741-0.11460.227-0.23620.0616-0.00890.1015-0.02380.06720.0183-0.0080.44328.46210.03116.086
34.1565-1.04461.16281.5662-2.7466.3760.1080.5706-0.4011-0.4494-0.01720.2880.8515-0.2421-0.09080.8159-0.3331-0.00170.2472-0.0850.6371-3.02657.317-2.263
43.9166-0.47580.61142.4981-0.39742.42780.053-0.2996-0.47190.3895-0.02-0.06740.09090.1051-0.0330.9312-0.37580.05910.1939-0.00520.656613.12650.35916.243
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A867 - 959
2X-RAY DIFFRACTION2A961 - 2000
3X-RAY DIFFRACTION3B867 - 959
4X-RAY DIFFRACTION4B961 - 2000

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