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- PDB-8i2n: The RIPK1 kinase domain in complex with QY7-2B compound -

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Basic information

Entry
Database: PDB / ID: 8i2n
TitleThe RIPK1 kinase domain in complex with QY7-2B compound
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE / RIPK1
Function / homology
Function and homology information


regulation of ATP:ADP antiporter activity / 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 / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death ...regulation of ATP:ADP antiporter activity / 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 / 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 / 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 / necroptotic signaling pathway / positive regulation of macrophage differentiation / T cell apoptotic process / JUN kinase kinase kinase activity / peptidyl-serine autophosphorylation / positive regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / RIP-mediated NFkB activation via ZBP1 / death-inducing signaling complex / negative regulation of necroptotic process / death receptor binding / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of programmed cell death / positive regulation of programmed necrotic cell death / TRP channels / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / necroptotic process / positive regulation of execution phase of apoptosis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / response to tumor necrosis factor / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic 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 / positive regulation of JNK cascade / Regulation of TNFR1 signaling / protein catabolic process / cellular response to growth factor stimulus / Regulation of necroptotic cell death / cellular response to hydrogen peroxide / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of neuron apoptotic process / positive regulation of reactive oxygen species metabolic process / positive regulation of tumor necrosis factor production / 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 / protein autophosphorylation / amyloid fibril formation / Potential therapeutics for SARS / receptor complex / non-specific serine/threonine protein kinase / protein kinase activity / endosome membrane / intracellular signal transduction / Ub-specific processing proteases / inflammatory response / positive regulation of apoptotic process / positive regulation of protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site ...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 / 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
Similarity search - Domain/homology
Chem-O4U / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsGong, X.Y. / Li, Y. / Meng, H.Y. / Pan, L.F.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21822705 China
CitationJournal: Acta Pharm Sin B / Year: 2024
Title: Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.
Authors: Qin, Y. / Li, D. / Qi, C. / Xiang, H. / Meng, H. / Liu, J. / Zhou, S. / Gong, X. / Li, Y. / Xu, G. / Zu, R. / Xie, H. / Xu, Y. / Xu, G. / Zhang, Z. / Chen, S. / Pan, L. / Li, Y. / Tan, L.
History
DepositionJan 14, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)67,8954
Polymers66,9372
Non-polymers9572
Water1,18966
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9472
Polymers33,4691
Non-polymers4791
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)33,9472
Polymers33,4691
Non-polymers4791
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.510, 98.742, 128.129
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 33468.730 Da / Num. of mol.: 2 / Mutation: C34A,C127A,C233A,C240A
Source method: isolated from a genetically manipulated source
Details: QY7-2B / 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-O4U / ~{N}-methyl-1-[4-[[[1-methyl-5-(phenylmethyl)pyrazol-3-yl]carbonylamino]methyl]phenyl]benzimidazole-5-carboxamide


Mass: 478.545 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H26N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 2.4 Å3/Da / Density % sol: 48.66 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 7.9
Details: 0.2 M Sodium chloride, 0.1 M Tris pH 7.9, 23% w/v Polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.29→78.21 Å / Num. obs: 27550 / % possible obs: 100 % / Redundancy: 12.9 % / Biso Wilson estimate: 48.42 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 14.9
Reflection shellResolution: 2.29→2.41 Å / Rmerge(I) obs: 1.216 / Num. unique obs: 3919

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata reduction
autoPROCdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITJ

4itj


Resolution: 2.29→32.3 Å / SU ML: 0.2885 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.5027
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2447 1345 4.9 %
Rwork0.2152 26122 -
obs0.2166 27467 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.05 Å2
Refinement stepCycle: LAST / Resolution: 2.29→32.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4277 0 72 66 4415
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01184442
X-RAY DIFFRACTIONf_angle_d1.71885995
X-RAY DIFFRACTIONf_chiral_restr0.0951655
X-RAY DIFFRACTIONf_plane_restr0.0112761
X-RAY DIFFRACTIONf_dihedral_angle_d15.01041671
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.29-2.370.30711310.26622564X-RAY DIFFRACTION100
2.37-2.460.28461230.26912581X-RAY DIFFRACTION100
2.46-2.570.3521130.26382583X-RAY DIFFRACTION99.96
2.57-2.710.28321430.25992570X-RAY DIFFRACTION100
2.71-2.880.2751430.2552570X-RAY DIFFRACTION99.96
2.88-3.10.33761440.27482599X-RAY DIFFRACTION100
3.1-3.410.30411370.2462586X-RAY DIFFRACTION100
3.41-3.910.23381390.20582633X-RAY DIFFRACTION100
3.91-4.920.19061370.17652642X-RAY DIFFRACTION100
4.92-32.30.20171350.18492794X-RAY DIFFRACTION99.63

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