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- PDB-6nyh: Structure of human RIPK1 kinase domain in complex with GNE684 -

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Basic information

Entry
Database: PDB / ID: 6nyh
TitleStructure of human RIPK1 kinase domain in complex with GNE684
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsIMMUNE SYSTEM / RIP1 / kinase / RIP / RIP1K RIPK1 / 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 / non-specific serine/threonine protein kinase / endosome membrane / 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 / protein-containing complex binding / positive regulation of gene expression / 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
IODIDE ION / Chem-L8D / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsFong, R. / Lupardus, P.J.
CitationJournal: Cell Death Differ. / Year: 2020
Title: RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases.
Authors: Patel, S. / Webster, J.D. / Varfolomeev, E. / Kwon, Y.C. / Cheng, J.H. / Zhang, J. / Dugger, D.L. / Wickliffe, K.E. / Maltzman, A. / Sujatha-Bhaskar, S. / Bir Kohli, P. / Ramaswamy, S. / ...Authors: Patel, S. / Webster, J.D. / Varfolomeev, E. / Kwon, Y.C. / Cheng, J.H. / Zhang, J. / Dugger, D.L. / Wickliffe, K.E. / Maltzman, A. / Sujatha-Bhaskar, S. / Bir Kohli, P. / Ramaswamy, S. / Deshmukh, G. / Liederer, B.M. / Fong, R. / Hamilton, G. / Lupardus, P. / Caplazi, P. / Lee, W.P. / van Lookeren Campagne, M. / Johnson, A. / McKenzie, B.S. / Junttila, M.R. / Newton, K. / Vucic, D.
History
DepositionFeb 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)68,85210
Polymers67,2262
Non-polymers1,6268
Water3,621201
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4265
Polymers33,6131
Non-polymers8134
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)34,4265
Polymers33,6131
Non-polymers8134
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.980, 97.034, 125.238
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


Mass: 33612.855 Da / Num. of mol.: 2 / Mutation: C34A, C127A, C233A, C240A
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-L8D / (5S)-N-[(3S)-7-methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide


Mass: 432.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N6O3
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.12 Å3/Da / Density % sol: 42.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1 M Bis Tris Propane buffer (pH 6.5), 0.2 M sodium iodide, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→48.52 Å / Num. obs: 32257 / % possible obs: 94.4 % / Redundancy: 5.7 % / Biso Wilson estimate: 30.2 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.106 / Net I/σ(I): 8.8
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.872 / Mean I/σ(I) obs: 1.6 / CC1/2: 0.723 / % possible all: 96.6

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Processing

Software
NameVersionClassification
PHENIX1.10.1-2155_2155refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITH

4ith


Resolution: 2.1→48.517 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.25
RfactorNum. reflection% reflection
Rfree0.2464 2154 6.69 %
Rwork0.2025 --
obs0.2056 32202 93.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→48.517 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4024 0 70 201 4295
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084176
X-RAY DIFFRACTIONf_angle_d0.9355639
X-RAY DIFFRACTIONf_dihedral_angle_d13.2922509
X-RAY DIFFRACTIONf_chiral_restr0.054628
X-RAY DIFFRACTIONf_plane_restr0.005706
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.14890.33351380.2712029X-RAY DIFFRACTION96
2.1489-2.20260.30181250.2581879X-RAY DIFFRACTION90
2.2026-2.26220.33581050.24441618X-RAY DIFFRACTION77
2.2622-2.32870.27531570.23262064X-RAY DIFFRACTION98
2.3287-2.40390.30171380.22942065X-RAY DIFFRACTION98
2.4039-2.48980.29731490.21922052X-RAY DIFFRACTION98
2.4898-2.58950.27191700.22692066X-RAY DIFFRACTION99
2.5895-2.70730.33021240.22181901X-RAY DIFFRACTION89
2.7073-2.85010.25591580.21712065X-RAY DIFFRACTION98
2.8501-3.02860.27311440.22662062X-RAY DIFFRACTION97
3.0286-3.26240.24521380.21261935X-RAY DIFFRACTION90
3.2624-3.59060.26651430.19391981X-RAY DIFFRACTION92
3.5906-4.110.2251370.16752009X-RAY DIFFRACTION94
4.11-5.17720.18741560.16152162X-RAY DIFFRACTION98
5.1772-48.52990.21881720.21022160X-RAY DIFFRACTION95

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