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- PDB-9mzy: Crystal structure of human RIPK1 with Compound 22 -

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Basic information

Entry
Database: PDB / ID: 9mzy
TitleCrystal structure of human RIPK1 with Compound 22
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 / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / 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 / ripoptosome / Defective RIPK1-mediated regulated necrosis / TRIF-mediated programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TLR3-mediated TICAM1-dependent programmed cell death / TNF signaling / Caspase activation via Death Receptors in the presence of ligand / programmed necrotic cell death / positive regulation of macrophage differentiation / SARS-CoV-1-mediated effects on programmed cell death / T cell apoptotic process / necroptotic signaling pathway / peptidyl-serine autophosphorylation / 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 / JUN kinase kinase kinase activity / 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 / positive regulation of execution phase of apoptosis / response to tumor necrosis factor / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / 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 / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to growth factor stimulus / Regulation of necroptotic cell death / cellular response to hydrogen peroxide / positive regulation of inflammatory response / positive regulation of reactive oxygen species metabolic process / positive regulation of NF-kappaB transcription factor activity / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / positive regulation of neuron apoptotic process / cellular response to tumor necrosis factor / positive regulation of protein phosphorylation / protein autophosphorylation / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of canonical NF-kappaB signal transduction / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / receptor complex / non-specific serine/threonine protein kinase / protein kinase activity / endosome membrane / Ub-specific processing proteases / intracellular signal transduction / positive regulation of apoptotic process / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process
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
: / GLYCINE / IODIDE ION / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 Å
AuthorsPalte, R.L. / Lesburg, C.A. / 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)66,51210
Polymers65,3322
Non-polymers1,1818
Water1,24369
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)47.307, 95.163, 128.121
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: 32665.777 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 , 5 types, 77 molecules

#2: Chemical ChemComp-A1BU6 / 1-[(2S,5S)-2,3-dihydro-2,5-methano-1,4-benzoxazepin-4(5H)-yl]-3,3-difluoro-2,2-dimethylpropan-1-one


Mass: 281.298 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17F2NO2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 2.21 Å3/Da / Density % sol: 44.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 20% (w/v) PEG3350; 6 mM Gly3; 0.22 M NH4I

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 1.0001 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Aug 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0001 Å / Relative weight: 1
ReflectionResolution: 2.32→76.4 Å / Num. obs: 25627 / % possible obs: 99.6 % / Redundancy: 7.9 % / CC1/2: 0.998 / Net I/σ(I): 16.5
Reflection shellResolution: 2.32→2.36 Å / Num. unique obs: 1226 / CC1/2: 0.962

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 31data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.32→76.4 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.922 / SU B: 27.576 / SU ML: 0.306 / Cross valid method: THROUGHOUT / ESU R: 0.558 / ESU R Free: 0.341 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31468 1034 4.5 %RANDOM
Rwork0.23913 ---
obs0.24247 22093 89.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 82.762 Å2
Baniso -1Baniso -2Baniso -3
1-1.72 Å20 Å20 Å2
2--3.63 Å2-0 Å2
3----5.35 Å2
Refinement stepCycle: LAST / Resolution: 2.32→76.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4359 0 50 69 4478
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0194352
X-RAY DIFFRACTIONr_bond_other_d0.0030.024204
X-RAY DIFFRACTIONr_angle_refined_deg1.581.9815890
X-RAY DIFFRACTIONr_angle_other_deg1.23539651
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.95538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.72724.798173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.78815.051779
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.1331514
X-RAY DIFFRACTIONr_chiral_restr0.090.2664
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214800
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02922
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_it5.2446.0452170
X-RAY DIFFRACTIONr_mcbond_other5.2456.0422169
X-RAY DIFFRACTIONr_mcangle_it7.5210.1782702
X-RAY DIFFRACTIONr_mcangle_other7.51910.182703
X-RAY DIFFRACTIONr_scbond_it5.1756.3132182
X-RAY DIFFRACTIONr_scbond_other5.1746.3132182
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.42710.5173189
X-RAY DIFFRACTIONr_long_range_B_refined9.72753.2034499
X-RAY DIFFRACTIONr_long_range_B_other9.72553.1714496
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 5856 / 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: 2.323→2.383 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.49 62 -
Rwork0.499 1272 -
obs--71.38 %
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)
14.7051.5568-2.9485.8623-2.26695.4268-0.3463-0.5018-0.74650.37160.03250.14720.5687-0.04520.31380.3745-0.03980.04110.1819-0.01190.520319.326-13.61454.745
20.22780.5426-0.98123.293-2.247.1125-0.0893-0.12540.04180.46310.00470.21480.157-0.11840.08470.40260.0940.00380.3999-0.02310.382117.929-4.57762.796
33.11280.1087-0.74513.13930.99013.86080.12320.03980.16270.01180.0586-0.2703-0.25380.2578-0.18190.1594-0.04560.02590.02730.00430.376628.39512.62852.418
42.6381-1.4827-0.16715.7136-1.61790.7633-0.034-0.14530.37570.2190.27520.3893-0.185-0.3714-0.24120.43010.16080.07310.6891-0.05070.53024.74322.34328.323
50.9405-0.25380.39234.8572.90592.07510.0293-0.6098-0.5402-0.4403-0.12620.7776-0.2424-0.49620.0970.4005-0.10590.04430.99480.31110.9735-4.62414.5523.36
61.61770.32381.7682.84061.36633.91510.2005-0.2028-0.0971-0.1395-0.1120.08060.2553-0.2896-0.08850.2113-0.05870.01880.11460.0710.34513.607-2.86322.151
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 95
2X-RAY DIFFRACTION2A155 - 176
3X-RAY DIFFRACTION3A96 - 154
4X-RAY DIFFRACTION3A188 - 294
5X-RAY DIFFRACTION4B8 - 95
6X-RAY DIFFRACTION5B155 - 180
7X-RAY DIFFRACTION6B96 - 154
8X-RAY DIFFRACTION6B188 - 294

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