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- PDB-6c3e: CRYSTAL STRUCTURE OF RIP1 KINASE BOUND TO INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 6c3e
TitleCRYSTAL STRUCTURE OF RIP1 KINASE BOUND TO INHIBITOR
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTransferase/Transferase Inhibitor / HUMAN RIP1 KINASE / CELL CYCLE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


regulation of ATP:ADP antiporter activity / ripoptosome assembly / positive regulation of interleukin-6-mediated signaling pathway / positive regulation of miRNA processing / ripoptosome assembly involved in necroptotic process / death domain binding / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death ...regulation of ATP:ADP antiporter activity / ripoptosome assembly / positive regulation of interleukin-6-mediated signaling pathway / positive regulation of miRNA processing / ripoptosome assembly involved in necroptotic process / death domain binding / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / programmed necrotic cell death / TNF signaling / Caspase activation via Death Receptors in the presence of ligand / T cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / positive regulation of macrophage differentiation / necroptotic signaling pathway / JUN kinase kinase kinase activity / peptidyl-serine autophosphorylation / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / positive regulation of necroptotic process / RIP-mediated NFkB activation via ZBP1 / death-inducing signaling complex / negative regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of programmed cell death / TRP channels / positive regulation of programmed necrotic cell death / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / positive regulation of execution phase of apoptosis / necroptotic process / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / response to tumor necrosis factor / signaling adaptor activity / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / tumor necrosis factor-mediated signaling pathway / TICAM1, RIP1-mediated IKK complex recruitment / IKK complex recruitment mediated by RIP1 / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of interleukin-8 production / negative regulation of extrinsic apoptotic signaling pathway / Regulation of TNFR1 signaling / positive regulation of JNK cascade / protein catabolic process / Regulation of necroptotic cell death / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of tumor necrosis factor production / positive regulation of reactive oxygen species metabolic process / positive regulation of neuron apoptotic process / Ovarian tumor domain proteases / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / positive regulation of canonical NF-kappaB signal transduction / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / protein autophosphorylation / receptor complex / endosome membrane / non-specific serine/threonine protein kinase / Ub-specific processing proteases / protein kinase activity / intracellular signal transduction / inflammatory response / positive regulation of protein phosphorylation / positive regulation of apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / ubiquitin protein ligase binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / ATP binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
RIP1, Death domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Death-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...RIP1, Death domain / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Death-like domain superfamily / 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 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
2-benzyl-5-nitro-1H-benzimidazole / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsSaikatendu, K.S. / Yoshikawa, M.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: ...Title: Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships.
Authors: Yoshikawa, M. / Saitoh, M. / Katoh, T. / Seki, T. / Bigi, S.V. / Shimizu, Y. / Ishii, T. / Okai, T. / Kuno, M. / Hattori, H. / Watanabe, E. / Saikatendu, K.S. / Zou, H. / Nakakariya, M. / ...Authors: Yoshikawa, M. / Saitoh, M. / Katoh, T. / Seki, T. / Bigi, S.V. / Shimizu, Y. / Ishii, T. / Okai, T. / Kuno, M. / Hattori, H. / Watanabe, E. / Saikatendu, K.S. / Zou, H. / Nakakariya, M. / Tatamiya, T. / Nakada, Y. / Yogo, T.
History
DepositionJan 9, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_radiation_wavelength.wavelength

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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 1
B: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6984
Polymers67,1922
Non-polymers5072
Water57632
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules

B: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6984
Polymers67,1922
Non-polymers5072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x+1/2,-y,z+1/21
Buried area1790 Å2
ΔGint-9 kcal/mol
Surface area23970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.262, 95.094, 134.444
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Receptor-interacting serine/threonine-protein kinase 1 / Cell death protein RIP / Receptor-interacting protein 1 / RIP-1 / Serine/threonine-protein kinase RIP


Mass: 33595.762 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK1, RIP, RIP1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13546, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-EJY / 2-benzyl-5-nitro-1H-benzimidazole


Mass: 253.256 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H11N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.01 Å3/Da / Density % sol: 38.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: 0.25 M ammonium iodide, 0.03 M glycyl-glycyl-glycine and polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 277 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 15973 / % possible obs: 95.7 % / Redundancy: 7.6 % / Net I/σ(I): 12.8
Reflection shellResolution: 2.6→2.66 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→44.83 Å / Cor.coef. Fo:Fc: 0.895 / Cor.coef. Fo:Fc free: 0.855 / SU B: 39.409 / SU ML: 0.375 / Cross valid method: THROUGHOUT / ESU R Free: 0.42 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30665 810 4.8 %RANDOM
Rwork0.259 ---
obs0.26138 15970 96.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 44.744 Å2
Baniso -1Baniso -2Baniso -3
1-0.34 Å2-0 Å20 Å2
2--0.03 Å2-0 Å2
3----0.37 Å2
Refinement stepCycle: 1 / Resolution: 2.6→44.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4117 0 38 32 4187
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0194249
X-RAY DIFFRACTIONr_bond_other_d0.0010.024155
X-RAY DIFFRACTIONr_angle_refined_deg1.0361.9895720
X-RAY DIFFRACTIONr_angle_other_deg0.74839603
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7115512
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.35924.633177
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.20715805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8041518
X-RAY DIFFRACTIONr_chiral_restr0.0620.2630
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214650
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02892
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4581.2092066
X-RAY DIFFRACTIONr_mcbond_other0.4531.2092065
X-RAY DIFFRACTIONr_mcangle_it0.6311.8132572
X-RAY DIFFRACTIONr_mcangle_other0.6311.8132573
X-RAY DIFFRACTIONr_scbond_it0.3661.2262183
X-RAY DIFFRACTIONr_scbond_other0.3661.2262172
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.4631.8333137
X-RAY DIFFRACTIONr_long_range_B_refined0.7779.4314699
X-RAY DIFFRACTIONr_long_range_B_other0.7789.4264690
X-RAY DIFFRACTIONr_rigid_bond_restr0.42938404
X-RAY DIFFRACTIONr_sphericity_free20.79514
X-RAY DIFFRACTIONr_sphericity_bonded1.47258336
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.437 62 -
Rwork0.294 1120 -
obs--93.36 %
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)
11.75830.0827-0.32343.05590.32311.79640.1016-0.0386-0.07520.09410.02290.0831-0.1331-0.0553-0.12450.25350.00230.01190.38520.02620.01949.8138-3.6097-23.4933
21.45660.04550.86123.4034-1.25993.2959-0.00790.14710.1002-0.38680.0046-0.05030.0407-0.05940.00330.3123-0.02520.01360.38190.02760.123622.031-2.5051-55.3044
31.82442.50580.32637.67690.00220.1489-0.08610.012-0.05630.1254-0.0409-0.4376-0.1056-0.05130.1270.13520.1326-0.13190.3738-0.0250.313511.4304-2.8196-42.2127
41.82880.3016-1.49561.80310.22751.3580.0476-0.04120.1072-0.22460.02360.1188-0.06330.0469-0.07120.2801-0.0135-0.0640.2783-0.0020.023717.2101-6.1868-34.3648
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A9 - 293
2X-RAY DIFFRACTION2B10 - 294
3X-RAY DIFFRACTION3A301
4X-RAY DIFFRACTION3B301
5X-RAY DIFFRACTION4A401 - 420
6X-RAY DIFFRACTION4B401 - 412

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