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- PDB-9q31: RIP1 kinase domain in complex with GDC-8264 -

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Basic information

Entry
Database: PDB / ID: 9q31
TitleRIP1 kinase domain in complex with GDC-8264
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE/Inhibitor / kinase / inhibitor / TRANSFERASE / TRANSFERASE-Inhibitor complex
Function / homology
Function and homology information


ripoptosome assembly / positive regulation of miRNA processing / positive regulation of interleukin-6-mediated signaling pathway / death domain binding / ripoptosome assembly involved in necroptotic process / T cell apoptotic process / programmed necrotic cell death / Defective RIPK1-mediated regulated necrosis / Microbial modulation of RIPK1-mediated regulated necrosis / tumor necrosis factor receptor superfamily complex ...ripoptosome assembly / positive regulation of miRNA processing / positive regulation of interleukin-6-mediated signaling pathway / death domain binding / ripoptosome assembly involved in necroptotic process / T cell apoptotic process / programmed necrotic cell death / Defective RIPK1-mediated regulated necrosis / Microbial modulation of RIPK1-mediated regulated necrosis / tumor necrosis factor receptor superfamily complex / TRIF-mediated programmed cell death / ripoptosome / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / activation of protein kinase activity / positive regulation of macrophage differentiation / TNF signaling / Caspase activation via Death Receptors in the presence of ligand / SARS-CoV-1-mediated effects on programmed cell death / necroptotic process / JUN kinase kinase kinase activity / necroptotic signaling pathway / negative regulation of necroptotic process / 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 / Dengue virus modulates apoptosis / positive regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / positive regulation of programmed necrotic cell death / positive regulation of extrinsic apoptotic signaling pathway / TNFR1-induced proapoptotic signaling / positive regulation of programmed cell death / RIPK1-mediated regulated necrosis / extrinsic apoptotic signaling pathway via death domain receptors / TRP channels / protein serine/threonine phosphatase activity / response to tumor necrosis factor / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of execution phase of apoptosis / extrinsic apoptotic signaling pathway / tumor necrosis factor-mediated signaling pathway / signaling adaptor activity / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of interleukin-8 production / negative regulation of canonical NF-kappaB signal transduction / canonical NF-kappaB signal transduction / TICAM1, RIP1-mediated IKK complex recruitment / protein serine/threonine kinase binding / cellular response to tumor necrosis factor / IKK complex recruitment mediated by RIP1 / intrinsic apoptotic signaling pathway in response to DNA damage / TNFR1-induced NF-kappa-B signaling pathway / Regulation of TNFR1 signaling / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of JNK cascade / cellular response to growth factor stimulus / Regulation of necroptotic cell death / positive regulation of reactive oxygen species metabolic process / positive regulation of neuron apoptotic process / positive regulation of inflammatory response / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / apoptotic process / inflammatory response / protein kinase activity / positive regulation of canonical NF-kappaB signal transduction / non-specific serine/threonine protein kinase / signaling receptor complex / intracellular signal transduction / Ub-specific processing proteases / endosome membrane / positive regulation of apoptotic process / protein serine kinase activity / ubiquitin protein ligase binding / protein serine/threonine kinase activity / positive regulation of gene expression / negative regulation of apoptotic process / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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 / 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
: / BROMIDE ION / PROPANE / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsLupardus, P. / Fong, R. / Demircioglu, F.E.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Clinical Candidate GDC-8264, a Novel, Potent and Selective RIP1 Inhibitor for Amelioration of Tissue Damage and the Treatment of Inflammatory Diseases.
Authors: Patel, S. / Chen, H. / Varfolomeev, E. / Kwon, Y. / Ramaswamy, S. / Kohli, P.B. / Quinn, J.G. / Webster, J.D. / Mao, J. / Chen, Y. / Fong, R. / Demircioglu, F.E. / Lupardus, P. / Stivala, C. ...Authors: Patel, S. / Chen, H. / Varfolomeev, E. / Kwon, Y. / Ramaswamy, S. / Kohli, P.B. / Quinn, J.G. / Webster, J.D. / Mao, J. / Chen, Y. / Fong, R. / Demircioglu, F.E. / Lupardus, P. / Stivala, C. / Hamilton, G.L. / Siu, M. / Sujatha-Bhaskar, S. / Mohanan, V. / Adedeji, A.O. / Santagostino, S.F. / Maher, J. / McKenzie, B. / Rothenberg, M.E. / Johnson, A. / Vucic, D.
History
DepositionAug 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2025Group: 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)68,44521
Polymers67,2262
Non-polymers1,22019
Water5,062281
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,21711
Polymers33,6131
Non-polymers60410
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)34,22810
Polymers33,6131
Non-polymers6159
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.368, 96.318, 127.757
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Receptor-interacting serine/threonine-protein kinase 1 / Cell death protein RIP / Receptor-interacting protein 1 / RIP-1


Mass: 33612.855 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

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Non-polymers , 6 types, 300 molecules

#2: Chemical ChemComp-A1CNU / cyclopropyl[(4R,5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone


Mass: 271.290 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H14FN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Br
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-TME / PROPANE


Mass: 44.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.17 Å3/Da / Density % sol: 43.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2M Na Bromide; 0.1M Bis Tris Propane, pH 6.5; 20% PEG 3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.05→38.95 Å / Num. obs: 37401 / % possible obs: 99.7 % / Redundancy: 13.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.026 / Rrim(I) all: 0.096 / Net I/σ(I): 18.6 / Num. measured all: 497151
Reflection shellResolution: 2.05→2.11 Å / % possible obs: 99.6 % / Redundancy: 13.2 % / Rmerge(I) obs: 0.891 / Num. measured all: 37680 / Num. unique obs: 2855 / CC1/2: 0.859 / Rpim(I) all: 0.252 / Rrim(I) all: 0.926 / Net I/σ(I) obs: 3.1

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PDB_EXTRACTdata extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→38.95 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.78 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.222 2475 6.63 %
Rwork0.1842 --
obs0.1868 37303 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.05→38.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4239 0 59 281 4579
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034442
X-RAY DIFFRACTIONf_angle_d0.556000
X-RAY DIFFRACTIONf_dihedral_angle_d4.704617
X-RAY DIFFRACTIONf_chiral_restr0.043664
X-RAY DIFFRACTIONf_plane_restr0.004786
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.090.30811310.23161890X-RAY DIFFRACTION99
2.09-2.130.281370.20721915X-RAY DIFFRACTION100
2.13-2.180.25681250.20741903X-RAY DIFFRACTION99
2.18-2.230.27781220.22821944X-RAY DIFFRACTION100
2.23-2.280.371310.30131892X-RAY DIFFRACTION98
2.28-2.350.25751290.20391920X-RAY DIFFRACTION100
2.35-2.420.28911380.20651912X-RAY DIFFRACTION100
2.42-2.490.26081370.20661909X-RAY DIFFRACTION98
2.49-2.580.27711540.20271878X-RAY DIFFRACTION100
2.58-2.690.25961240.20131962X-RAY DIFFRACTION100
2.69-2.810.26191380.19571920X-RAY DIFFRACTION100
2.81-2.960.22751420.20391944X-RAY DIFFRACTION100
2.96-3.140.27241480.20991938X-RAY DIFFRACTION100
3.14-3.380.24541430.19281920X-RAY DIFFRACTION99
3.38-3.720.17911350.16581954X-RAY DIFFRACTION100
3.72-4.260.18751410.14621977X-RAY DIFFRACTION100
4.26-5.370.16131360.14251981X-RAY DIFFRACTION98
5.37-38.950.18641640.17822069X-RAY DIFFRACTION99
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)
18.0910.5036-1.61415.7837-1.27864.09210.3598-0.45880.70390.1738-0.0677-0.3208-0.5591-0.1447-0.23770.3829-0.00010.05570.2334-0.06780.395817.410928.622638.9304
22.78471.9609-0.42085.5079-0.68541.6820.0643-0.10910.28740.05980.019-0.2958-0.2466-0.0043-0.08590.21610.0258-0.00320.2074-0.02460.228514.405912.966936.1025
31.23080.14141.28533.1505-0.84542.0828-0.0202-0.22560.05460.214-0.0581-0.383-0.17990.2522-0.0130.2236-0.0051-0.04810.26620.00310.215720.3011-1.591545.9708
45.0319-1.57341.84533.3216-1.69913.71160.0144-0.235-0.34890.00860.1110.20960.307-0.4991-0.14650.2407-0.0796-0.03070.2118-0.00970.26575.9073-8.731238.7582
51.96930.8542-1.6974.51612.80195.0163-0.72170.4118-0.8271-0.48620.401-1.22921.09790.34590.17420.86390.06210.23870.58090.00910.63144.4577-15.81717.6071
62.04440.2717-0.66834.33320.27552.7041-0.30110.1236-0.296-0.24480.2425-0.18530.67480.11020.03190.34980.01650.0520.2384-0.00440.2081-1.795-1.091512.3073
73.0851-0.657-1.33042.47230.57274.45140.05640.11920.1503-0.08190.0568-0.0479-0.256-0.0663-0.13690.1890.0070.02820.15240.01240.1947-4.921316.71938.1211
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 7 through 53 )
2X-RAY DIFFRACTION2chain 'A' and (resid 54 through 170 )
3X-RAY DIFFRACTION3chain 'A' and (resid 171 through 243 )
4X-RAY DIFFRACTION4chain 'A' and (resid 244 through 294 )
5X-RAY DIFFRACTION5chain 'B' and (resid 9 through 69 )
6X-RAY DIFFRACTION6chain 'B' and (resid 70 through 170 )
7X-RAY DIFFRACTION7chain 'B' and (resid 171 through 294 )

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