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- PDB-6c4d: Structure based design of RIP1 kinase inhibitors -

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Basic information

Entry
Database: PDB / ID: 6c4d
TitleStructure based design of RIP1 kinase inhibitors
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTransferase/Transferase Inhibitor / HUMAN RIPK1 KINASE / CELL CYCLE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


ripoptosome assembly / positive regulation of miRNA processing / positive regulation of interleukin-6-mediated signaling pathway / ripoptosome assembly involved in necroptotic process / death domain binding / peptidyl-serine autophosphorylation / ripoptosome / Defective RIPK1-mediated regulated necrosis / TNF signaling / Microbial modulation of RIPK1-mediated regulated necrosis ...ripoptosome assembly / positive regulation of miRNA processing / positive regulation of interleukin-6-mediated signaling pathway / ripoptosome assembly involved in necroptotic process / death domain binding / peptidyl-serine autophosphorylation / ripoptosome / Defective RIPK1-mediated regulated necrosis / TNF signaling / Microbial modulation of RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / programmed necrotic cell death / Caspase activation via Death Receptors in the presence of ligand / SARS-CoV-1-mediated effects on programmed cell death / positive regulation of macrophage differentiation / JUN kinase kinase kinase activity / T cell apoptotic process / necroptotic signaling pathway / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / RIP-mediated NFkB activation via ZBP1 / positive regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of necroptotic process / death receptor binding / positive regulation of programmed cell death / positive regulation of programmed necrotic cell death / positive regulation of extrinsic apoptotic signaling pathway / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / TRP channels / necroptotic process / response to tumor necrosis factor / canonical NF-kappaB signal transduction / positive regulation of execution phase of apoptosis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / TICAM1, RIP1-mediated IKK complex recruitment / tumor necrosis factor-mediated signaling pathway / IKK complex recruitment mediated by RIP1 / negative regulation of extrinsic apoptotic signaling pathway / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of interleukin-8 production / positive regulation of JNK cascade / protein catabolic process / Regulation of TNFR1 signaling / positive regulation of non-canonical NF-kappaB signal transduction / : / Regulation of necroptotic cell death / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / positive regulation of reactive oxygen species metabolic process / positive regulation of protein phosphorylation / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / cellular response to tumor necrosis factor / Ovarian tumor domain proteases / positive regulation of neuron apoptotic process / protein autophosphorylation / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / receptor complex / protein kinase activity / non-specific serine/threonine protein kinase / endosome membrane / Ub-specific processing proteases / intracellular signal transduction / positive regulation of apoptotic process / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / protein-containing complex binding / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EJP / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.52 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 11, 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 / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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


Theoretical massNumber of molelcules
Total (without water)136,2318
Polymers134,3834
Non-polymers1,8484
Water82946
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0582
Polymers33,5961
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0582
Polymers33,5961
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0582
Polymers33,5961
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0582
Polymers33,5961
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.768, 138.133, 95.933
Angle α, β, γ (deg.)90.00, 96.08, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 4
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-EJP / (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile


Mass: 461.900 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H20ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.24 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.2
Details: 0.25 M ammonium iodide, 0.03 M glycyl-glycyl-glycine and polyethylene glycol (PEG) 3350 15-25%

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Data collection

DiffractionMean temperature: 85 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 29, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.52→95.39 Å / Num. obs: 37759 / % possible obs: 99 % / Redundancy: 3.6 % / Net I/σ(I): 12.9
Reflection shellResolution: 2.52→2.58 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementResolution: 2.52→95.39 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.882 / SU B: 45.254 / SU ML: 0.419 / Cross valid method: THROUGHOUT / ESU R Free: 0.38 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29643 1976 5 %RANDOM
Rwork0.23625 ---
obs0.24554 37639 98.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 71.72 Å2
Baniso -1Baniso -2Baniso -3
1--3.85 Å2-0 Å21.04 Å2
2---0.99 Å2-0 Å2
3---4.52 Å2
Refinement stepCycle: 1 / Resolution: 2.52→95.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8471 0 132 46 8649
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0198788
X-RAY DIFFRACTIONr_bond_other_d0.0010.028586
X-RAY DIFFRACTIONr_angle_refined_deg0.9461.99511846
X-RAY DIFFRACTIONr_angle_other_deg0.964319841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.43551044
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.5524.854377
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.993151660
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.471536
X-RAY DIFFRACTIONr_chiral_restr0.0570.21292
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0219745
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021901
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_it3.6176.6314215
X-RAY DIFFRACTIONr_mcbond_other3.6176.6314214
X-RAY DIFFRACTIONr_mcangle_it4.8819.9335246
X-RAY DIFFRACTIONr_mcangle_other4.889.9345247
X-RAY DIFFRACTIONr_scbond_it3.2286.7564573
X-RAY DIFFRACTIONr_scbond_other3.2286.7564573
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.90710.0596601
X-RAY DIFFRACTIONr_long_range_B_refined5.11351.3659746
X-RAY DIFFRACTIONr_long_range_B_other5.11151.3659746
X-RAY DIFFRACTIONr_rigid_bond_restr4.237317374
X-RAY DIFFRACTIONr_sphericity_free49.268514
X-RAY DIFFRACTIONr_sphericity_bonded32.738517221
LS refinement shellResolution: 2.52→2.585 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 124 -
Rwork0.371 2533 -
obs--91.09 %
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)
10.1173-0.08440.12490.1314-0.02110.2008-0.01130.00180.00660.02220.0115-0.0128-0.00480.0078-0.00020.0894-0.0002-0.00830.0738-0.00090.00177.7871-0.071.6757
20.0154-0.0338-0.02850.0840.07220.0859-0.0097-0.0014-0.00190.00830.00130.01320.00920.00020.00840.08720.0004-0.00590.0679-0.0010.030729.050632.6539-7.8517
30.0563-0.0070.02510.0892-0.06530.19410.00030.0060.0001-0.00160.00260.0063-0.00840.0052-0.00290.0910.0022-0.00560.0674-0.00370.0164-6.95337.319147.4547
40.1447-0.015-0.15410.1216-0.07180.5398-0.0090.0163-0.0145-0.00580.0161-0.00020.024-0.0502-0.00710.0867-0-0.00280.07230.00590.01863.718840.057841.7476
50.00210.00140.00380.00190.00240.00690.0036-0.0037-0.0007-0.0025-0.0042-0.0050.0062-0.00830.00050.07880.00280.00140.05960.00260.033410.11819.422721.1361
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 294
2X-RAY DIFFRACTION2B7 - 294
3X-RAY DIFFRACTION3C10 - 294
4X-RAY DIFFRACTION4D5 - 293
5X-RAY DIFFRACTION5A1201 - 1214
6X-RAY DIFFRACTION5B1201 - 1211
7X-RAY DIFFRACTION5C1201 - 1213
8X-RAY DIFFRACTION5D1201 - 1208

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