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- PDB-6ul8: RIP2 kinase catalytic domain complex with (5S,6S,8R)-2-(benzo[d]t... -

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Basic information

Entry
Database: PDB / ID: 6ul8
TitleRIP2 kinase catalytic domain complex with (5S,6S,8R)-2-(benzo[d]thiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamide
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTRANSFERASE / Kinase
Function / homology
Function and homology information


response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / caspase binding / positive regulation of T-helper 1 type immune response / CARD domain binding / positive regulation of xenophagy / xenophagy ...response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / caspase binding / positive regulation of T-helper 1 type immune response / CARD domain binding / positive regulation of xenophagy / xenophagy / LIM domain binding / positive regulation of protein K63-linked ubiquitination / nucleotide-binding oligomerization domain containing 1 signaling pathway / cellular response to muramyl dipeptide / positive regulation of stress-activated MAPK cascade / positive regulation of immature T cell proliferation in thymus / CD4-positive, alpha-beta T cell proliferation / JUN kinase kinase kinase activity / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / activation of cysteine-type endopeptidase activity / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of macrophage cytokine production / toll-like receptor 4 signaling pathway / response to exogenous dsRNA / positive regulation of interferon-alpha production / cellular response to lipoteichoic acid / canonical NF-kappaB signal transduction / lipopolysaccharide-mediated signaling pathway / signaling adaptor activity / stress-activated MAPK cascade / positive regulation of chemokine production / JNK cascade / positive regulation of interleukin-12 production / positive regulation of interleukin-2 production / p75NTR recruits signalling complexes / positive regulation of interferon-beta production / ERK1 and ERK2 cascade / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of interleukin-1 beta production / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein ubiquitination / activated TAK1 mediates p38 MAPK activation / non-specific protein-tyrosine kinase / positive regulation of JNK cascade / non-membrane spanning protein tyrosine kinase activity / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / protein homooligomerization / cytokine-mediated signaling pathway / Interleukin-1 signaling / positive regulation of interleukin-6 production / positive regulation of type II interferon production / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / positive regulation of protein binding / Downstream TCR signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / positive regulation of canonical NF-kappaB signal transduction / vesicle / adaptive immune response / positive regulation of ERK1 and ERK2 cascade / cytoskeleton / non-specific serine/threonine protein kinase / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / positive regulation of apoptotic process / innate immune response / signaling receptor binding / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 ...Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-Q9J / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsShewchuk, L.M. / Convery, M.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.
Authors: Haffner, C.D. / Charnley, A.K. / Aquino, C.J. / Casillas, L. / Convery, M.A. / Cox, J.A. / Elban, M.A. / Goodwin, N.C. / Gough, P.J. / Haile, P.A. / Hughes, T.V. / Knapp-Reed, B. / ...Authors: Haffner, C.D. / Charnley, A.K. / Aquino, C.J. / Casillas, L. / Convery, M.A. / Cox, J.A. / Elban, M.A. / Goodwin, N.C. / Gough, P.J. / Haile, P.A. / Hughes, T.V. / Knapp-Reed, B. / Kreatsoulas, C. / Lakdawala, A.S. / Li, H. / Lian, Y. / Lipshutz, D. / Mehlmann, J.F. / Ouellette, M. / Romano, J. / Shewchuk, L. / Shu, A. / Votta, B.J. / Zhou, H. / Bertin, J. / Marquis, R.W.
History
DepositionOct 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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 / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry / _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: Receptor-interacting serine/threonine-protein kinase 2
B: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1405
Polymers70,3892
Non-polymers7513
Water2,180121
1
A: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5502
Polymers35,1941
Non-polymers3551
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5903
Polymers35,1941
Non-polymers3952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.677, 125.677, 105.760
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B
13A
23B

NCS domain segments:

Component-ID: 1 / Refine code: 4

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUCYSCYSAA66 - 16862 - 164
21GLUGLUCYSCYSBB66 - 16862 - 164
12LYSLYSPROPROAA209 - 228205 - 224
22LYSLYSPROPROBB209 - 228205 - 224
13PROPROLEULEUAA248 - 290244 - 286
23PROPROLEULEUBB248 - 290244 - 286

NCS ensembles :
ID
1
2
3

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.536427, -0.52122, -0.663758), (-0.534449, -0.398888, 0.745153), (-0.653154, 0.754465, -0.064591)54.423069, -9.31279, 46.0308
3given(1), (1), (1)
4given(-0.530876, -0.48159, -0.69731), (-0.558533, -0.42, 0.715291), (-0.637347, 0.769202, -0.046016)54.164639, -8.99788, 45.908581
5given(1), (1), (1)
6given(-0.551111, -0.487396, -0.67729), (-0.554545, -0.39257, 0.733736), (-0.623504, 0.779958, -0.053933)55.49033, -8.4901, 45.453758

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Components

#1: Protein Receptor-interacting serine/threonine-protein kinase 2 / CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ...CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ICE-kinase / RIP-like-interacting CLARP kinase / Receptor-interacting protein 2 / RIP-2 / Tyrosine-protein kinase RIPK2


Mass: 35194.465 Da / Num. of mol.: 2 / Mutation: C7S, S168C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: unidentified baculovirus
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-Q9J / (5S,6S,8R)-2-(1,3-benzothiazol-5-yl)-6-hydroxy-4,5,6,7,8,9-hexahydro-5,8-methanopyrazolo[1,5-a][1,3]diazocine-3-carboxamide


Mass: 355.414 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H17N5O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O
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: 3.71 Å3/Da / Density % sol: 66.85 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 85 mM Tris, pH 7.5, 200 mM calcium chloride, 10% PEG400, 5% glycerol, in 24 well Linbro trays at 22 degrees C. Crystals were frozen directly from the tray using paraffin oil as a cryoprotectant.

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.9 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 11, 2015
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.68→105.76 Å / Num. obs: 27463 / % possible obs: 100 % / Redundancy: 7.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.044 / Rrim(I) all: 0.12 / Net I/σ(I): 12 / Num. measured all: 196550
Reflection shell

Diffraction-ID: 1 / Resolution: 2.68→2.83 Å

Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
7.20.65439440.8520.2610.705100
6.20.0599490.9970.0240.06499.4

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Processing

Software
NameVersionClassification
Aimless0.5.17data scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5AR2

5ar2


Resolution: 2.68→75.85 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.929 / SU B: 19.997 / SU ML: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.39 / ESU R Free: 0.253
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.22 1312 4.8 %RANDOM
Rwork0.1831 ---
obs0.1849 26118 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 140.35 Å2 / Biso mean: 65.189 Å2 / Biso min: 32.22 Å2
Baniso -1Baniso -2Baniso -3
1-0.99 Å20.49 Å20 Å2
2--0.99 Å2-0 Å2
3----3.2 Å2
Refinement stepCycle: final / Resolution: 2.68→75.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4444 0 51 121 4616
Biso mean--51.69 49.48 -
Num. residues----562
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194639
X-RAY DIFFRACTIONr_bond_other_d0.0020.024268
X-RAY DIFFRACTIONr_angle_refined_deg1.3911.9626332
X-RAY DIFFRACTIONr_angle_other_deg0.95139891
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6925561
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.97523.781201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.3415751
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0711525
X-RAY DIFFRACTIONr_chiral_restr0.0750.2716
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215064
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02915
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
11626MEDIUM POSITIONAL0.220.5
11626MEDIUM THERMAL3.952
2336MEDIUM POSITIONAL0.330.5
2336MEDIUM THERMAL3.592
3682MEDIUM POSITIONAL0.360.5
3682MEDIUM THERMAL6.192
LS refinement shellResolution: 2.682→2.751 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 83 -
Rwork0.256 1941 -
all-2024 -
obs--99.95 %
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)
10.39910.27010.26591.3118-0.851.1473-0.0304-0.07550.023-0.02220.10510.12810.0376-0.2197-0.07470.0876-0.03130.02660.16380.01760.024945.592-40.2154.062
20.0835-0.31140.19811.416-0.79991.3993-0.0266-0.0423-0.0213-0.07310.09470.1769-0.2269-0.0373-0.06810.15420.0364-0.05010.0385-0.01030.071448.773-14.693-14.351
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 310
2X-RAY DIFFRACTION2B5 - 310

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