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- PDB-7xmk: Crystal structure of human RIPK1 kinase domain in complex with co... -

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Basic information

Entry
Database: PDB / ID: 7xmk
TitleCrystal structure of human RIPK1 kinase domain in complex with compound SKLB923
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE / RIPK1 / kinase / complex / inhibitor
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 tumor necrosis factor production / Ovarian tumor domain proteases / positive regulation of neuron apoptotic process / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / protein autophosphorylation / response to oxidative stress / positive regulation of protein phosphorylation / amyloid fibril formation / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / eukaryotic translation initiation factor 2alpha kinase activity / 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 / Ub-specific processing proteases / endosome membrane / 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
Chem-GO4 / IODIDE ION / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.376 Å
AuthorsZhang, L. / Wang, Y. / Li, Y. / Yang, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases.
Authors: Zhang, L. / Li, Y. / Tian, C. / Yang, R. / Wang, Y. / Xu, H. / Zhu, Q. / Chen, S. / Li, L. / Yang, S.
History
DepositionApr 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)68,1846
Polymers66,9372
Non-polymers1,2474
Water2,540141
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)68,1846
Polymers66,9372
Non-polymers1,2474
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_654-x+3/2,-y,z-1/21
Buried area1740 Å2
ΔGint-10 kcal/mol
Surface area24100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.885, 100.904, 127.594
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: 33468.730 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13546, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-GO4 / 5-[2-(cyclopropylcarbonylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-N-[(1S)-1-(3-fluorophenyl)ethyl]-1-methyl-indole-3-carboxamide


Mass: 496.536 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C28H25FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.35 Å3/Da / Density % sol: 47.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.25M ammonium iodide, 0.03M glycyl-glycyl-glycine, 23% polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL18U / Wavelength: 0.97915 Å
DetectorType: DECTRIS PILATUS3 X CdTe 1M / Detector: PIXEL / Date: Feb 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.37→50 Å / Num. obs: 26140 / % possible obs: 100 % / Redundancy: 10 % / Biso Wilson estimate: 35.15 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 25.727
Reflection shellResolution: 2.37→2.41 Å / Num. unique obs: 1259 / CC1/2: 0.699

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITJ

4itj


Resolution: 2.376→30.415 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2585 1301 5.02 %
Rwork0.2243 24602 -
obs0.226 25903 98.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 106.47 Å2 / Biso mean: 39.648 Å2 / Biso min: 14.18 Å2
Refinement stepCycle: final / Resolution: 2.376→30.415 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4116 0 126 141 4383
Biso mean--30 38.22 -
Num. residues----511
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3762-2.47130.32631360.28092483261991
2.4713-2.58370.33181390.26852694283399
2.5837-2.71980.29621650.261927042869100
2.7198-2.89010.30191320.256527402872100
2.8901-3.1130.27251610.248227182879100
3.113-3.42590.24671520.234127352887100
3.4259-3.92080.25151460.211627682914100
3.9208-4.93640.22321380.188628132951100
4.9364-30.4150.23251320.209129473079100

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