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- PDB-9hy9: Crystal structure of an allosteric inhibitor bound to human RIPK1... -

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Basic information

Entry
Database: PDB / ID: 9hy9
TitleCrystal structure of an allosteric inhibitor bound to human RIPK1 kinase domain
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsIMMUNE SYSTEM / RIPK1 / kinase / 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 / peptidyl-serine autophosphorylation / ripoptosome / Defective RIPK1-mediated regulated necrosis / TNF signaling / Microbial modulation of RIPK1-mediated regulated necrosis ...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 / TNF signaling / 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 / 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 / positive regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of necroptotic process / 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 / canonical NF-kappaB signal transduction / positive regulation of execution phase of apoptosis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / TICAM1, RIP1-mediated IKK complex recruitment / tumor necrosis factor-mediated signaling pathway / IKK complex recruitment mediated by RIP1 / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of interleukin-8 production / TNFR1-induced NF-kappa-B signaling pathway / protein catabolic process / Regulation of TNFR1 signaling / positive regulation of non-canonical NF-kappaB signal transduction / : / positive regulation of JNK cascade / Regulation of necroptotic cell death / cellular response to growth factor stimulus / positive regulation of reactive oxygen species metabolic process / cellular response to hydrogen peroxide / positive regulation of protein phosphorylation / positive regulation of tumor necrosis factor production / positive regulation of inflammatory response / 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 / protein kinase activity / positive regulation of canonical NF-kappaB signal transduction / receptor complex / non-specific serine/threonine protein kinase / endosome membrane / intracellular signal transduction / Ub-specific processing proteases / 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 / cytosol / cytoplasm
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
: / IODIDE ION / DI(HYDROXYETHYL)ETHER / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsMaskos, K. / Johannsson, S. / Kempf, G. / Neumann, L. / Cross, J.B.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Rsc Med Chem / Year: 2025
Title: Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization.
Authors: Vijayan, R.S.K. / Hamilton, M.M. / Pfaffinger, D.E. / Alvarez, F.G. / Reyna, N.J. / Bardenhagen, J.P. / Shepard, H. / Rodriguez, C. / Goodwani, S. / Lightfoot, Y. / Maskos, K. / Johannsson, ...Authors: Vijayan, R.S.K. / Hamilton, M.M. / Pfaffinger, D.E. / Alvarez, F.G. / Reyna, N.J. / Bardenhagen, J.P. / Shepard, H. / Rodriguez, C. / Goodwani, S. / Lightfoot, Y. / Maskos, K. / Johannsson, S. / Kempf, G. / Xu, Q.A. / Neumann, L. / Jiang, Y. / Do, M.G. / Jones, P. / Lewis, R.T. / Ray, W.J. / Cross, J.B.
History
DepositionJan 9, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2026Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)69,59814
Polymers67,3402
Non-polymers2,25812
Water1,36976
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint4 kcal/mol
Surface area25390 Å2
Unit cell
Length a, b, c (Å)47.582, 98.129, 127.126
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: 33669.906 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-A1IX9 / ~{N}-[(1~{S})-1-(2-chloranyl-6-fluoranyl-phenyl)ethyl]-4-fluoranyl-1-[2-fluoranyl-5-(1-methylpyrazol-4-yl)phenyl]carbonyl-piperidine-4-carboxamide


Mass: 504.932 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24ClF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.2 Å3/Da / Density % sol: 44.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 6 mM Gly3 29 %w/v PEG 3350 0,25 M NH4I

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.29→77.68 Å / Num. obs: 123845 / % possible obs: 96.9 % / Redundancy: 4.63 % / CC1/2: 0.99 / Net I/σ(I): 19.02
Reflection shellResolution: 2.29→2.54 Å / Num. unique obs: 7202 / Rsym value: 45

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.29→77.68 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.92 / SU B: 17.735 / SU ML: 0.22 / Cross valid method: THROUGHOUT / ESU R: 0.344 / ESU R Free: 0.26 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2751 1211 4.5 %RANDOM
Rwork0.21695 ---
obs0.21947 25527 96.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 71.547 Å2
Baniso -1Baniso -2Baniso -3
1--0.58 Å2-0 Å20 Å2
2--0.73 Å2-0 Å2
3----0.15 Å2
Refinement stepCycle: LAST / Resolution: 2.29→77.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4143 0 86 76 4305
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194113
X-RAY DIFFRACTIONr_bond_other_d0.0050.023934
X-RAY DIFFRACTIONr_angle_refined_deg1.6941.9935574
X-RAY DIFFRACTIONr_angle_other_deg1.27939003
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4485509
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.81824.518166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.61615.058694
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.971515
X-RAY DIFFRACTIONr_chiral_restr0.1040.2629
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214566
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02881
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.0414.1992057
X-RAY DIFFRACTIONr_mcbond_other4.0354.1972056
X-RAY DIFFRACTIONr_mcangle_it5.5857.0562556
X-RAY DIFFRACTIONr_mcangle_other5.5857.0572557
X-RAY DIFFRACTIONr_scbond_it5.1534.6772056
X-RAY DIFFRACTIONr_scbond_other5.1434.6772056
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.0597.6933018
X-RAY DIFFRACTIONr_long_range_B_refined8.6337.9154338
X-RAY DIFFRACTIONr_long_range_B_other8.63137.8754333
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 5544 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.03 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.29→2.349 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 92 -
Rwork0.342 1882 -
obs--98.9 %
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)
11.98891.68370.30918.7166-3.52883.12690.0496-0.1639-0.67860.11380.09810.44140.6163-0.4234-0.14780.6732-0.06460.20530.5053-0.02390.605518.98-13.22853.384
24.15995.9687-2.42598.7624-3.51191.44380.14350.01320.04490.5645-0.0270.1908-0.1343-0.0774-0.11640.6993-0.00330.14590.49510.03860.392917.632-4.00562.041
32.4540.5547-0.27693.12381.1024.08690.0110.13090.071-0.06780.0437-0.3574-0.1640.3432-0.05480.2577-0.02630.01380.28380.06720.07528.90912.80351.866
43.8445-1.6402-0.99466.2802-1.05562.84430.08830.45980.4259-0.26780.27450.7166-0.4656-0.6363-0.36290.54840.01180.06970.47620.03130.35495.01623.32226.667
52.3248-3.4209-2.94995.11884.33343.76110.25180.5712-0.3856-0.4359-0.68860.8717-0.2844-0.86080.43690.5677-0.1128-0.24651.34250.66051.2041-4.58916.65523.158
62.46291.14841.01174.04491.51263.84130.01290.0597-0.0534-0.07220.0873-0.06580.18910.1666-0.10010.31120.06720.01350.30980.00590.004213.535-2.5721.717
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A10 - 102
2X-RAY DIFFRACTION2A162 - 169
3X-RAY DIFFRACTION3A103 - 161
4X-RAY DIFFRACTION3A188 - 294
5X-RAY DIFFRACTION4B8 - 102
6X-RAY DIFFRACTION5B162 - 176
7X-RAY DIFFRACTION6B103 - 161
8X-RAY DIFFRACTION6B188 - 294

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