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- PDB-6nw2: Structure of human RIPK1 kinase domain in complex with compound 11 -

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Basic information

Entry
Database: PDB / ID: 6nw2
TitleStructure of human RIPK1 kinase domain in complex with compound 11
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTransferase/Transferase inhibitor / RIP1 / kinase / RIP / RIP1K RIPK1 / IMMUNE SYSTEM / 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 / ripoptosome / Defective RIPK1-mediated regulated necrosis / Microbial modulation of RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death ...: / ripoptosome assembly / positive regulation of miRNA processing / positive regulation of interleukin-6-mediated signaling pathway / ripoptosome assembly involved in necroptotic process / death domain binding / ripoptosome / Defective RIPK1-mediated regulated necrosis / Microbial modulation of RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TNF signaling / 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 / T cell apoptotic process / necroptotic signaling pathway / peptidyl-serine autophosphorylation / positive regulation of necroptotic process / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / RIP-mediated NFkB activation via ZBP1 / JUN kinase kinase kinase activity / negative regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / positive regulation of programmed cell death / positive regulation of programmed necrotic cell death / positive regulation of extrinsic apoptotic signaling pathway / TRP channels / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / necroptotic process / positive regulation of execution phase of apoptosis / response to tumor necrosis factor / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of canonical NF-kappaB signal transduction / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / signaling adaptor activity / 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 / positive regulation of JNK cascade / Regulation of TNFR1 signaling / protein catabolic process / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to growth factor stimulus / Regulation of necroptotic cell death / cellular response to hydrogen peroxide / positive regulation of inflammatory response / positive regulation of reactive oxygen species metabolic process / positive regulation of tumor necrosis factor production / positive regulation of neuron apoptotic process / Ovarian tumor domain proteases / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / protein autophosphorylation / positive regulation of canonical NF-kappaB signal transduction / amyloid fibril formation / response to oxidative stress / Potential therapeutics for SARS / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / positive regulation of protein phosphorylation / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / receptor complex / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / endosome membrane / Ub-specific processing proteases / positive regulation of apoptotic process / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-L4Y / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsFong, R. / Lupardus, P.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group.
Authors: Hamilton, G.L. / Chen, H. / Deshmukh, G. / Eigenbrot, C. / Fong, R. / Johnson, A. / Kohli, P.B. / Lupardus, P.J. / Liederer, B.M. / Ramaswamy, S. / Wang, H. / Wang, J. / Xu, Z. / Zhu, Y. / Vucic, D. / Patel, S.
History
DepositionFeb 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1May 15, 2019Group: 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

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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)71,5584
Polymers70,8502
Non-polymers7092
Water3,621201
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7792
Polymers35,4251
Non-polymers3541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7792
Polymers35,4251
Non-polymers3541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.862, 96.644, 125.285
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: 35424.832 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-L4Y / (5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide


Mass: 354.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H22N4O3
#3: 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: 1.96 Å3/Da / Density % sol: 37.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1M Bis Tris Propane pH 6.5, 0.2M Sodium Iodide, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 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: 1 Å / Relative weight: 1
ReflectionResolution: 2→48.32 Å / Num. obs: 38557 / % possible obs: 100 % / Redundancy: 7.7 % / Biso Wilson estimate: 30.7 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Net I/σ(I): 13.1
Reflection shellResolution: 2→2.05 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.868 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2812 / CC1/2: 0.794 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.10.1-2155_2155refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→45.085 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2613 2557 6.65 %
Rwork0.2088 --
obs0.2123 38458 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→45.085 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4017 0 52 201 4270
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074176
X-RAY DIFFRACTIONf_angle_d0.9135634
X-RAY DIFFRACTIONf_dihedral_angle_d14.3312527
X-RAY DIFFRACTIONf_chiral_restr0.056626
X-RAY DIFFRACTIONf_plane_restr0.006705
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.03850.3441420.26571942X-RAY DIFFRACTION100
2.0385-2.08010.32561380.24121998X-RAY DIFFRACTION100
2.0801-2.12530.2761380.23511942X-RAY DIFFRACTION100
2.1253-2.17480.27871240.23121986X-RAY DIFFRACTION100
2.1748-2.22920.40731230.2811983X-RAY DIFFRACTION100
2.2292-2.28940.4031430.31671970X-RAY DIFFRACTION99
2.2894-2.35680.33411390.22241940X-RAY DIFFRACTION100
2.3568-2.43290.26111350.20971994X-RAY DIFFRACTION100
2.4329-2.51980.29251580.20551954X-RAY DIFFRACTION100
2.5198-2.62070.2421410.21781987X-RAY DIFFRACTION100
2.6207-2.73990.31340.21671982X-RAY DIFFRACTION100
2.7399-2.88440.27851500.22441998X-RAY DIFFRACTION100
2.8844-3.06510.30131460.23461993X-RAY DIFFRACTION100
3.0651-3.30160.27881480.21571989X-RAY DIFFRACTION100
3.3016-3.63380.25161390.19912000X-RAY DIFFRACTION100
3.6338-4.15930.20411440.18522051X-RAY DIFFRACTION100
4.1593-5.2390.22351460.16522044X-RAY DIFFRACTION100
5.239-45.09620.22671690.19562148X-RAY DIFFRACTION100

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