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- PDB-7fd0: Crystal Structure of human RIPK1 kinase domain in complex with a ... -

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Basic information

Entry
Database: PDB / ID: 7fd0
TitleCrystal Structure of human RIPK1 kinase domain in complex with a novel inhibitor
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsIMMUNE SYSTEM/INHIBITOR / IMMUNE SYSTEM-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 / Ovarian tumor domain proteases / positive regulation of neuron apoptotic process / 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 / endosome membrane / non-specific serine/threonine protein kinase / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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 / 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-3IU / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsSu, H.X. / Xie, H. / Nie, T.Q. / Li, M.J. / Xu, Y.C.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2022
Title: Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis.
Authors: Yang, X. / Lu, H. / Xie, H. / Zhang, B. / Nie, T. / Fan, C. / Yang, T. / Xu, Y. / Su, H. / Tang, W. / Zhou, B.
History
DepositionJul 15, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 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)68,3394
Polymers67,3682
Non-polymers9712
Water3,945219
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)68,3394
Polymers67,3682
Non-polymers9712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_454-x-1/2,-y,z-1/21
Buried area1510 Å2
ΔGint-10 kcal/mol
Surface area22870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.832, 98.330, 125.958
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: 33683.930 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: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q13546, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3IU / N-[(3S)-5-methyl-7-[2-(oxan-4-yl)ethynyl]-4-oxidanylidene-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(phenylmethyl)-4H-1,2,4-triazole-3-carboxamide


Mass: 485.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / 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: 2.15 Å3/Da / Density % sol: 42.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.25 M ammonium iodide, 0.03 M glycyl-glycyl-glycine and 15-25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 39912 / % possible obs: 99.7 % / Redundancy: 12 % / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.017 / Rrim(I) all: 0.06 / Χ2: 0.899 / Net I/σ(I): 10.4 / Num. measured all: 480589
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2-2.0310.71.21619770.7510.3851.2770.88599.7
2.03-2.0710.40.99319350.7560.3271.0480.91100
2.07-2.1112.30.89419640.8750.2620.9320.911100
2.11-2.1512.30.69719800.9220.2050.7270.91699.9
2.15-2.212.30.5719580.9440.1680.5950.87699.9
2.2-2.2512.20.46119910.9640.1360.4820.99499.9
2.25-2.31120.35419900.9720.1050.370.90299.9
2.31-2.3711.90.29319560.9760.0880.3070.92499.9
2.37-2.4411.70.23419750.9850.0710.2450.93199.6
2.44-2.5210.80.1919620.9840.0610.20.9599.3
2.52-2.6112.60.1619870.9920.0460.1660.95299.7
2.61-2.7112.50.12219800.9940.0350.1270.97599.9
2.71-2.8412.50.09419750.9960.0270.0980.96399.9
2.84-2.9912.40.07620020.9960.0220.080.97499.6
2.99-3.17120.06119860.9960.0180.0630.97499
3.17-3.4211.90.04820030.9980.0140.050.93999.3
3.42-3.7613.10.04220160.9980.0120.0430.88199.6
3.76-4.3112.90.03620420.9980.010.0380.79599.7
4.31-5.4312.20.03420550.9990.010.0360.71899.3
5.43-5012.10.03421780.9990.010.0360.65899.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.29 Å31.7 Å
Translation4.29 Å31.7 Å

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
HKL-2000data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITH

4ith


Resolution: 2→49.17 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2655 1921 4.95 %
Rwork0.2311 36893 -
obs0.2328 38814 96.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 87.52 Å2 / Biso mean: 32.6319 Å2 / Biso min: 8.1 Å2
Refinement stepCycle: final / Resolution: 2→49.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4018 0 72 219 4309
Biso mean--22.97 32.28 -
Num. residues----523
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.050.26891080.24232001210974
2.05-2.110.28021380.24632419255792
2.11-2.170.32411200.25282612273297
2.17-2.240.30331460.24482639278598
2.24-2.320.26951050.250526922797100
2.32-2.410.27431320.24926862818100
2.41-2.520.30621510.2462658280999
2.52-2.660.271530.252726792832100
2.66-2.820.2981420.256126932835100
2.82-3.040.26891370.259927102847100
3.04-3.350.29221320.24072723285599
3.35-3.830.23981540.210427152869100
3.83-4.820.21781690.18542742291199
4.82-49.170.26421340.22612924305899
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)
14.8644-0.99241.87444.61580.4557.16790.32430.0562-0.3857-0.27330.2976-0.54850.74760.1834-0.63160.3589-0.0435-0.03070.2114-0.06620.3548-7.1694-26.470221.4083
28.4255-3.937-0.87472.1818-0.12494.7761-0.0114-0.60870.18070.74190.5924-1.62260.19980.635-0.4370.32340.017-0.35870.2944-0.10370.88851.7315-20.382135.2057
35.7378-5.2588-1.32748.77972.43924.5339-0.0574-0.082-0.39270.30080.418-0.55440.52380.1588-0.3250.2077-0.0386-0.0850.1461-0.02340.3638-6.9816-20.258329.5731
44.493-0.54080.88695.9789-0.58324.30110.01950.2419-0.4066-0.3460.24390.29690.1188-0.4504-0.22720.1509-0.0483-0.00180.15470.05350.1608-16.9256-6.534223.9504
51.62510.89590.0434.5338-1.86783.46120.09170.1733-0.2734-0.2263-0.0884-0.977-0.18070.47760.00330.1866-0.03140.09410.1821-0.0220.361-3.81-0.847222.9282
62.7290.8363-1.76183.1123-1.75746.45950.24590.406-0.7192-1.3144-0.1102-0.5815-0.0080.3437-0.02330.4739-0.0670.3290.11730.0580.241-4.92866.74489.5442
74.0625-0.0803-2.33973.7017-0.66274.12280.10170.26940.3882-0.07140.16160.2813-0.6544-0.6428-0.26590.34710.07740.11850.17510.07250.2542-17.39849.435524.5587
82.6309-1.11260.04293.4947-1.39955.3149-0.513-0.05760.96630.43120.0915-0.4505-1.47230.21060.09460.63070.0226-0.14860.2166-0.08150.4388-24.320718.519252.2646
91.4190.33430.4282.6781.37713.4751-0.2448-0.20610.54520.12010.173-0.3493-0.68560.310.15150.4299-0.076-0.12680.2388-0.0650.3619-17.045810.851155.7948
103.02480.93310.41475.61040.55714.0617-0.1854-0.07280.41720.14560.11440.3038-0.5738-0.41890.07410.24450.0446-0.0310.19230.07030.1738-27.4307-2.793550.1521
113.09341.1865-0.54283.49690.00586.90230.02280.0615-0.08530.06780.0773-0.05690.3637-0.4755-0.09390.0956-0.0374-0.07670.12160.06040.1594-28.6656-17.595254.1731
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 53 )A9 - 53
2X-RAY DIFFRACTION2chain 'A' and (resid 54 through 69 )A54 - 69
3X-RAY DIFFRACTION3chain 'A' and (resid 70 through 93 )A70 - 93
4X-RAY DIFFRACTION4chain 'A' and (resid 94 through 154 )A94 - 154
5X-RAY DIFFRACTION5chain 'A' and (resid 155 through 223 )A155 - 223
6X-RAY DIFFRACTION6chain 'A' and (resid 224 through 242 )A224 - 242
7X-RAY DIFFRACTION7chain 'A' and (resid 243 through 294 )A243 - 294
8X-RAY DIFFRACTION8chain 'B' and (resid 10 through 39 )B10 - 39
9X-RAY DIFFRACTION9chain 'B' and (resid 40 through 93 )B40 - 93
10X-RAY DIFFRACTION10chain 'B' and (resid 94 through 188 )B94 - 188
11X-RAY DIFFRACTION11chain 'B' and (resid 189 through 294 )B189 - 294

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