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- PDB-9mzx: Crystal structure of human RIPK1 with Compound 1 -

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Basic information

Entry
Database: PDB / ID: 9mzx
TitleCrystal structure of human RIPK1 with Compound 1
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE/INHIBITOR / Kinase / serine/threonine-protein 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 / 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 / positive regulation of macrophage differentiation / SARS-CoV-1-mediated effects on programmed cell death / T cell apoptotic process / JUN kinase kinase kinase activity / necroptotic signaling pathway / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / death-inducing signaling complex / positive regulation of necroptotic process / RIP-mediated NFkB activation via ZBP1 / 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 extrinsic apoptotic signaling pathway / positive regulation of programmed necrotic cell death / 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 / TICAM1, RIP1-mediated IKK complex recruitment / signaling adaptor activity / IKK complex recruitment mediated by RIP1 / negative regulation of canonical NF-kappaB signal transduction / TNFR1-induced NF-kappa-B signaling pathway / Regulation of TNFR1 signaling / tumor necrosis factor-mediated signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of interleukin-8 production / positive regulation of JNK cascade / Regulation of necroptotic cell death / 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 / cellular response to hydrogen peroxide / positive regulation of protein phosphorylation / Ovarian tumor domain proteases / positive regulation of inflammatory response / positive regulation of reactive oxygen species metabolic process / positive regulation of tumor necrosis factor production / cellular response to tumor necrosis factor / positive regulation of neuron apoptotic process / protein autophosphorylation / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / endosome membrane / receptor complex / positive regulation of canonical NF-kappaB signal transduction / Ub-specific processing proteases / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / positive regulation of apoptotic process / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / apoptotic process / 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 / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsLesburg, C.A. / Palte, R.L. / Maskos, K. / Thomsen, M. / Lammens, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1.
Authors: Chen, J.L. / Methot, J.L. / Mitcheltree, M.J. / Musacchio, A. / Corcoran, E.B. / Feng, G. / Lammens, A. / Maskos, K. / Palte, R.L. / Rickard, M.M. / Otte, K.M. / Mansueto, M.S. / Venkat, S. ...Authors: Chen, J.L. / Methot, J.L. / Mitcheltree, M.J. / Musacchio, A. / Corcoran, E.B. / Feng, G. / Lammens, A. / Maskos, K. / Palte, R.L. / Rickard, M.M. / Otte, K.M. / Mansueto, M.S. / Venkat, S. / Sondey, C. / Thomsen, M. / Lesburg, C.A. / Fradera, X. / Fell, M.J. / DiMauro, E.F. / Siliphaivanh, P.
History
DepositionJan 23, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 28, 2025Provider: repository / Type: Initial release

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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)67,11111
Polymers65,7322
Non-polymers1,3799
Water46826
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.407, 101.124, 130.664
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: 32866.012 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-A1BU4 / 1-[(2S,5S)-2,3-dihydro-2,5-methano-1,4-benzoxazepin-4(5H)-yl]-2,2-dimethylpropan-1-one


Mass: 245.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H19NO2 / 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.: 26 / 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: 2.53 Å3/Da / Density % sol: 51.44 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 20% (w/v) PEG3350; 6 mM Gly3; 0.01 m NaAcetate pH 4.75; 0.12 M Na3Citrate; 0.28 M NH4I

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.53→79.97 Å / Num. obs: 18320 / % possible obs: 100 % / Redundancy: 8.2 % / CC1/2: 0.997 / Net I/σ(I): 10.7
Reflection shellResolution: 2.53→79.97 Å / Num. unique obs: 890 / CC1/2: 0.408

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 26data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.53→79.97 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.921 / SU B: 27.875 / SU ML: 0.279 / Cross valid method: THROUGHOUT / ESU R: 0.904 / ESU R Free: 0.342 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26284 832 4.4 %RANDOM
Rwork0.21493 ---
obs0.21707 18178 83.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 76.691 Å2
Baniso -1Baniso -2Baniso -3
1--1.14 Å20 Å20 Å2
2--2.32 Å2-0 Å2
3----1.19 Å2
Refinement stepCycle: LAST / Resolution: 2.53→79.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4277 0 43 26 4346
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194164
X-RAY DIFFRACTIONr_bond_other_d0.0030.023989
X-RAY DIFFRACTIONr_angle_refined_deg1.5341.9785660
X-RAY DIFFRACTIONr_angle_other_deg1.24539094
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0815529
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.5324.403159
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.57815.058687
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.061515
X-RAY DIFFRACTIONr_chiral_restr0.0860.2651
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214656
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02903
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_it4.3646.1892130
X-RAY DIFFRACTIONr_mcbond_other4.3656.1882129
X-RAY DIFFRACTIONr_mcangle_it6.74910.442654
X-RAY DIFFRACTIONr_mcangle_other6.74710.4412655
X-RAY DIFFRACTIONr_scbond_it4.2626.272034
X-RAY DIFFRACTIONr_scbond_other4.2616.272035
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.48210.4713007
X-RAY DIFFRACTIONr_long_range_B_refined9.00855.0424377
X-RAY DIFFRACTIONr_long_range_B_other9.00755.0444378
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 5852 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.04 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.535→2.6 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 5 -
Rwork0.299 85 -
obs--5.52 %
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)
16.2291-1.25413.319110.5745-1.91513.1692-0.18920.90640.4845-0.7270.10980.0816-0.13740.27590.07940.1523-0.00430.02570.23050.01930.2242-5.36613.97912.776
20.4405-0.0518-0.55770.1334-0.72515.69340.04320.36080.1158-0.0383-0.1425-0.06490.04410.21890.09920.24040.00530.02910.41920.0550.2518-4.8537.3073.285
33.5125-0.54150.53924.19950.70745.44490.21750.2069-0.1122-0.0763-0.0468-0.19430.64430.5404-0.17060.1320.0721-0.08070.0690.01050.20194.807-11.03814.437
47.97194.4681-1.22857.3868-0.80291.6205-0.03460.3188-0.7665-0.17890.27150.08430.3964-0.1862-0.2370.25620.0034-0.10460.0718-0.01930.242-19.738-23.08137.063
510.6816.8509-2.18766.15691.6265.68330.39040.57570.0950.4239-0.177-0.04390.137-1.0986-0.21330.28280.0784-0.0420.26680.1110.4869-28.838-17.16142.92
62.51-1.6116-1.91165.55840.53345.95710.0607-0.17870.26560.17590.1455-0.0504-0.62680.1072-0.20610.2116-0.0094-0.01260.03170.02720.1416-12.3092.04344.979
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 95
2X-RAY DIFFRACTION2A155 - 170
3X-RAY DIFFRACTION3A96 - 154
4X-RAY DIFFRACTION3A188 - 294
5X-RAY DIFFRACTION4B6 - 95
6X-RAY DIFFRACTION5B155 - 170
7X-RAY DIFFRACTION6B96 - 154
8X-RAY DIFFRACTION6B188 - 294

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