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- PDB-7ydx: Crystal structure of human RIPK1 kinase domain in complex with co... -

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Basic information

Entry
Database: PDB / ID: 7ydx
TitleCrystal structure of human RIPK1 kinase domain in complex with compound RI-962
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE / RIPK1 / kinase / complex / inhibitor
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 / 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 / peptidyl-serine autophosphorylation / ripoptosome / Defective RIPK1-mediated regulated necrosis / 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 / 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 / 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 / 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 / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / TRP channels / necroptotic process / response to tumor necrosis factor / positive regulation of execution phase of apoptosis / canonical NF-kappaB signal transduction / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway / signaling adaptor activity / negative regulation of canonical NF-kappaB signal transduction / TICAM1, RIP1-mediated IKK complex recruitment / IKK complex recruitment mediated by RIP1 / tumor necrosis factor-mediated signaling pathway / 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 / positive regulation of NF-kappaB transcription factor activity / cellular response to growth factor stimulus / Regulation of necroptotic cell death / cellular response to hydrogen peroxide / positive regulation of protein phosphorylation / positive regulation of reactive oxygen species metabolic process / 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 / non-specific serine/threonine protein kinase / receptor complex / protein kinase activity / 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 / cytoplasm / 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-3CI / IODIDE ION / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.642 Å
AuthorsZhang, L. / Wang, Y. / Li, Y. / Wu, C. / Luo, X. / Wang, T. / Lei, J. / Yang, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2022
Title: Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor.
Authors: Li, Y. / Zhang, L. / Wang, Y. / Zou, J. / Yang, R. / Luo, X. / Wu, C. / Yang, W. / Tian, C. / Xu, H. / Wang, F. / Yang, X. / Li, L. / Yang, S.
History
DepositionJul 4, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)68,78711
Polymers66,9372
Non-polymers1,8499
Water1,17165
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)68,78711
Polymers66,9372
Non-polymers1,8499
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_454-x-1/2,-y,z-1/21
Buried area2380 Å2
ΔGint-10 kcal/mol
Surface area24480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.569, 97.530, 132.377
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 33468.730 Da / Num. of mol.: 2 / Mutation: C34A,C217A,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-3CI / 1-methyl-5-[2-(2-methylpropanoylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-N-[(1S)-1-phenylethyl]indole-3-carboxamide


Mass: 480.561 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.29 Å3/Da / Density % sol: 46.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.25M ammonium iodide, 0.03M glycyl-glycyl-glycine, 23% polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS3 X CdTe 1M / Detector: PIXEL / Date: Jan 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.64→50 Å / Num. obs: 18712 / % possible obs: 100 % / Redundancy: 11.3 % / Biso Wilson estimate: 40.17 Å2 / Rmerge(I) obs: 0.071 / Net I/σ(I): 36
Reflection shellResolution: 2.64→2.7 Å / Mean I/σ(I) obs: 2.167 / Num. unique obs: 873 / CC1/2: 0.781

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITJ

4itj


Resolution: 2.642→48.765 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 29.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2892 1844 10 %
Rwork0.2603 16589 -
obs0.2632 18433 98.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 99.09 Å2 / Biso mean: 42.1556 Å2 / Biso min: 16.35 Å2
Refinement stepCycle: final / Resolution: 2.642→48.765 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4229 0 79 65 4373
Biso mean--29.75 42.05 -
Num. residues----532
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6422-2.71360.34291140.32271026114082
2.7136-2.79350.39911400.3071261140198
2.7935-2.88360.3331390.327412451384100
2.8836-2.98670.37661430.32912961439100
2.9867-3.10620.34681410.315712601401100
3.1062-3.24760.36551430.299112841427100
3.2476-3.41880.39361420.287212871429100
3.4188-3.63290.32831430.263612861429100
3.6329-3.91330.27981450.248712941439100
3.9133-4.30690.2471430.230313011444100
4.3069-4.92960.18971460.211813071453100
4.9296-6.20880.2481480.243313281476100
6.2088-48.7650.25271570.228914141571100
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)
10.3320.249-0.40262.29010.38491.3756-0.0616-0.0497-0.18660.09890.0998-0.18440.10660.0079-0.03020.19020.0106-0.07130.2174-0.03670.2289-8.9844-15.864226.1282
2-0.0521-0.24210.18140.9043-0.3386-0.0221-0.712-0.036-0.4241-0.37410.1371-0.8683-0.49431.1907-0.0134-0.026-0.0041-0.15060.3315-0.07420.4973.4697-6.879520.6015
30.85640.0767-0.51191.2213-0.36641.20350.37680.26680.27710.15560.0421-0.03-0.8068-0.4328-0.03340.35270.1095-0.12840.2512-0.02350.1503-13.82097.691919.2075
41.0289-0.6812-0.11292.114-0.26920.9941-0.0136-0.07870.12580.33130.0015-0.0214-0.11580.0199-0.00970.2117-0.01760.00470.23590.02690.2049-22.79295.649752.6043
51.26590.14160.32941.1494-0.07572.04680.1626-0.0235-0.15780.10970.02280.30210.5003-0.2297-0.02580.2727-0.0385-0.03810.19020.03030.3095-27.6789-16.641654.6388
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 8 through 154 )A8 - 154
2X-RAY DIFFRACTION2chain 'A' and (resid 155 through 206 )A155 - 206
3X-RAY DIFFRACTION3chain 'A' and (resid 207 through 294 )A207 - 294
4X-RAY DIFFRACTION4chain 'B' and (resid 9 through 170 )B9 - 170
5X-RAY DIFFRACTION5chain 'B' and (resid 171 through 294 )B171 - 294

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