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

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Basic information

Entry
Database: PDB / ID: 7fcz
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 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-3IF / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.21 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)68,2514
Polymers67,3682
Non-polymers8832
Water1,47782
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)68,2514
Polymers67,3682
Non-polymers8832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x+1/2,-y,z+1/21
Buried area1210 Å2
ΔGint-9 kcal/mol
Surface area23720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.674, 101.705, 129.907
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 / 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: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q13546, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3IF / N-[(3S)-7-(2-cyclopropylethynyl)-5-methyl-4-oxidanylidene-2,3-dihydro-1,5-benzoxazepin-3-yl]-5-(phenylmethyl)-4H-1,2,4-triazole-3-carboxamide


Mass: 441.482 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H23N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.09 Å3/Da / Density % sol: 41.21 %
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: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 29171 / % possible obs: 99.9 % / Redundancy: 12.3 % / Rmerge(I) obs: 0.234 / Rpim(I) all: 0.069 / Rrim(I) all: 0.244 / Χ2: 0.985 / Net I/σ(I): 4.1 / Num. measured all: 357851
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.2-2.2410.31.2214410.6190.4051.2890.94699.9
2.24-2.2810.71.12113920.6760.3631.1810.96799.9
2.28-2.32111.00114320.7420.3211.0530.946100
2.32-2.3711.40.98614410.7670.3091.0340.981100
2.37-2.4211.80.96714260.8080.2971.0130.982100
2.42-2.4812.30.92414310.8650.2770.9650.991100
2.48-2.5412.50.87114600.8980.2580.911.014100
2.54-2.6112.60.79414310.8720.2330.8291.009100
2.61-2.6912.10.64914400.9060.1950.6781.04100
2.69-2.7712.20.56514430.9450.1680.591.043100
2.77-2.8712.40.4914420.9630.1450.5121.024100
2.87-2.9913.70.42214510.9730.1190.4391.042100
2.99-3.1213.60.34614430.9830.0970.3591.026100
3.12-3.2913.40.25714750.9890.0720.2671.075100
3.29-3.4913.30.19314600.9920.0550.2011.081100
3.49-3.7612.70.14214700.9930.0410.1481.062100
3.76-4.1411.80.10814780.9960.0330.1131.052100
4.14-4.7413.10.08314920.9970.0240.0870.984100
4.74-5.97130.07915180.9980.0230.0820.81100
5.97-5011.30.04816050.9990.0150.050.59499

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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: 2.21→30.05 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2567 1450 5.08 %
Rwork0.2345 27066 -
obs0.2356 28516 97.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 88.4 Å2 / Biso mean: 38.4808 Å2 / Biso min: 14.05 Å2
Refinement stepCycle: final / Resolution: 2.21→30.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3937 0 148 0 4085
Biso mean--33.03 --
Num. residues----511
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.21-2.280.30651250.27152260238583
2.28-2.380.29761580.26312570272894
2.38-2.480.29031380.26362642278097
2.48-2.620.31691470.26552712285999
2.62-2.780.30321310.250727482879100
2.78-2.990.29911380.265427832921100
2.99-3.290.28081520.255827862938100
3.29-3.770.24381480.22627752923100
3.77-4.750.20031500.196528573007100
4.75-30.050.23291630.220429333096100
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)
12.63191.07121.09886.31472.08173.1395-0.2758-0.03940.69050.11780.1984-0.2075-0.69630.07740.11460.3949-0.0158-0.08850.2787-0.01030.39324.471714.6246-11.2955
21.38690.53861.18053.28761.31352.49390.00220.20530.38010.0695-0.34080.803-0.242-0.88480.30830.30590.0923-0.02460.5288-0.14890.4739-13.51121.7182-15.3662
32.20980.14781.35162.02130.21885.16680.0645-0.3264-0.07440.2847-0.19880.04250.2531-0.55450.13580.1866-0.0479-0.00250.2616-0.02050.189-4.4848-10.0192-9.3065
45.5092-0.61031.11271.65042.28647.6015-0.38450.0166-0.12610.9187-0.6162-0.2244-0.2889-0.13280.70390.6743-0.0395-0.06520.22220.11970.465513.483-31.9474-32.4397
55.6161-0.48992.10721.73010.5412.9594-0.05740.4214-0.14440.2517-0.02850.0431-0.13620.21580.04910.4364-0.0374-0.08550.1530.02990.428414.3724-27.64-39.1238
63.9424-2.607-0.49476.8567-0.10170.12440.1958-0.5269-0.4869-0.13740.1826-0.25730.1379-0.0011-0.29920.3235-0.0393-0.08820.21860.02080.244817.3576-20.5604-28.7025
72.6675-1.9942-0.64115.34420.21521.62450.21580.0876-0.4025-0.4245-0.03830.23410.4871-0.4784-0.20640.3331-0.0744-0.10250.2303-0.02360.24896.6717-15.0464-42.9359
82.5445-0.0297-0.2663.0507-0.02114.29970.093-0.1298-0.22390.04920.03840.1010.2877-0.1864-0.11620.1827-0.0067-0.00140.17330.0270.17878.3553-6.2397-34.8963
94.4031.44721.81092.7432-0.62833.40770.3485-0.3703-0.33730.2351-0.2005-0.71340.20150.5669-0.18250.27870.0498-0.07350.3549-0.0260.304324.0683-17.0869-36.2684
102.0627-1.60160.61341.2249-0.51590.93120.28830.90080.0209-0.0488-0.2341-0.45710.61321.3921-0.07750.32380.04010.03270.47920.00610.454525.2906-1.8733-42.6896
112.37561.2736-0.42253.2926-1.25245.2549-0.0360.31360.1427-0.23250.2006-0.08350.31640.2571-0.1050.20380.0077-0.01280.1641-0.01390.211716.13263.266-47.3836
122.0073-0.6199-1.39963.1765-1.32265.8170.12810.1880.3446-0.07570.29110.4427-0.6758-0.6285-0.44010.26130.0380.04580.20830.06330.327411.495710.2506-41.9075
132.07980.04012.13482.69040.22264.34240.3412-0.72040.55520.196-0.07250.3474-0.3724-0.6124-0.28330.26040.00720.01740.26430.00950.31881.60535.1488-30.3547
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 10 through 93 )A10 - 93
2X-RAY DIFFRACTION2chain 'A' and (resid 94 through 111 )A94 - 111
3X-RAY DIFFRACTION3chain 'A' and (resid 112 through 294 )A112 - 294
4X-RAY DIFFRACTION4chain 'B' and (resid 7 through 22 )B7 - 22
5X-RAY DIFFRACTION5chain 'B' and (resid 23 through 57 )B23 - 57
6X-RAY DIFFRACTION6chain 'B' and (resid 58 through 86 )B58 - 86
7X-RAY DIFFRACTION7chain 'B' and (resid 87 through 111 )B87 - 111
8X-RAY DIFFRACTION8chain 'B' and (resid 112 through 154 )B112 - 154
9X-RAY DIFFRACTION9chain 'B' and (resid 155 through 168 )B155 - 168
10X-RAY DIFFRACTION10chain 'B' and (resid 169 through 206 )B169 - 206
11X-RAY DIFFRACTION11chain 'B' and (resid 207 through 242 )B207 - 242
12X-RAY DIFFRACTION12chain 'B' and (resid 243 through 277 )B243 - 277
13X-RAY DIFFRACTION13chain 'B' and (resid 278 through 294 )B278 - 294

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