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- PDB-6rln: Crystal structure of RIP1 kinase in complex with GSK3145095 -

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Basic information

Entry
Database: PDB / ID: 6rln
TitleCrystal structure of RIP1 kinase in complex with GSK3145095
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE / Inhibitor / Complex
Function / homology
Function and homology information


regulation of ATP:ADP antiporter activity / 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 / TLR3-mediated TICAM1-dependent programmed cell death ...regulation of ATP:ADP antiporter activity / 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 / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / TNF signaling / programmed necrotic cell death / Caspase activation via Death Receptors in the presence of ligand / SARS-CoV-1-mediated effects on programmed cell death / necroptotic signaling pathway / positive regulation of macrophage differentiation / T cell apoptotic process / JUN kinase kinase kinase activity / peptidyl-serine autophosphorylation / positive regulation of necroptotic process / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / RIP-mediated NFkB activation via ZBP1 / death-inducing signaling complex / negative regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of programmed cell death / positive regulation of programmed necrotic cell death / TRP channels / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / necroptotic process / positive regulation of execution phase of apoptosis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / response to tumor necrosis factor / negative regulation of canonical NF-kappaB signal transduction / signaling adaptor activity / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / 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 / Regulation of necroptotic cell death / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of neuron apoptotic process / positive regulation of reactive oxygen species metabolic process / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / cellular response to tumor necrosis factor / positive regulation of NF-kappaB transcription factor activity / positive regulation of canonical NF-kappaB signal transduction / response to oxidative stress / amyloid fibril formation / Potential therapeutics for SARS / protein autophosphorylation / receptor complex / non-specific serine/threonine protein kinase / endosome membrane / protein kinase activity / intracellular signal transduction / Ub-specific processing proteases / inflammatory response / positive regulation of apoptotic process / positive regulation of protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / apoptotic process / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / ATP binding / identical protein binding / plasma membrane / cytosol
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 / Transferase(Phosphotransferase) domain 1 ...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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-K8K / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.87 Å
AuthorsThorpe, J.H. / Harris, P.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.
Authors: Harris, P.A. / Marinis, J.M. / Lich, J.D. / Berger, S.B. / Chirala, A. / Cox, J.A. / Eidam, P.M. / Finger, J.N. / Gough, P.J. / Jeong, J.U. / Kang, J. / Kasparcova, V. / Leister, L.K. / ...Authors: Harris, P.A. / Marinis, J.M. / Lich, J.D. / Berger, S.B. / Chirala, A. / Cox, J.A. / Eidam, P.M. / Finger, J.N. / Gough, P.J. / Jeong, J.U. / Kang, J. / Kasparcova, V. / Leister, L.K. / Mahajan, M.K. / Miller, G. / Nagilla, R. / Ouellette, M.T. / Reilly, M.A. / Rendina, A.R. / Rivera, E.J. / Sun, H.H. / Thorpe, J.H. / Totoritis, R.D. / Wang, W. / Wu, D. / Zhang, D. / Bertin, J. / Marquis, R.W.
History
DepositionMay 2, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)69,9894
Polymers69,1942
Non-polymers7952
Water45025
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9942
Polymers34,5971
Non-polymers3971
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)34,9942
Polymers34,5971
Non-polymers3971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)101.840, 130.790, 48.830
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 / Serine/threonine-protein kinase RIP


Mass: 34596.891 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: Baculovirus expression vector pFastBac1-HM
References: UniProt: Q13546, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-K8K / ~{N}-[(3~{S})-7,9-bis(fluoranyl)-2-oxidanylidene-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-3-(phenylmethyl)-1~{H}-1,2,4-triazole-5-carboxamide


Mass: 397.378 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H17F2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / Source method: isolated from a natural source / Formula: H2O

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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: 47.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 100mM MES (pH 6.5), 25% PEG 8k

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976251 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 30, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976251 Å / Relative weight: 1
ReflectionResolution: 2.87→55.03 Å / Num. obs: 15475 / % possible obs: 99.4 % / Redundancy: 6.4 % / Biso Wilson estimate: 107.07 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.027 / Rrim(I) all: 0.07 / Net I/σ(I): 17.6
Reflection shellResolution: 2.87→2.97 Å / Redundancy: 6.5 % / Rmerge(I) obs: 1.094 / Num. unique obs: 1420 / CC1/2: 0.657 / Rpim(I) all: 0.497 / Rrim(I) all: 1.291 / % possible all: 95.3

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITJ

4itj


Resolution: 2.87→55.03 Å / Cor.coef. Fo:Fc: 0.9403 / Cor.coef. Fo:Fc free: 0.9201 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.35
RfactorNum. reflection% reflectionSelection details
Rfree0.2318 777 5.04 %RANDOM
Rwork0.1939 ---
obs0.1957 15428 99.24 %-
Displacement parametersBiso mean: 99.26 Å2
Baniso -1Baniso -2Baniso -3
1-8.7459 Å20 Å20 Å2
2--19.9493 Å20 Å2
3----28.6952 Å2
Refine analyzeLuzzati coordinate error obs: 0.456 Å
Refinement stepCycle: 1 / Resolution: 2.87→55.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4277 0 58 25 4360
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014427HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.225966HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1584SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes115HARMONIC2
X-RAY DIFFRACTIONt_gen_planes615HARMONIC5
X-RAY DIFFRACTIONt_it4427HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion20.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion564SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5024SEMIHARMONIC4
LS refinement shellResolution: 2.87→3.07 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.3057 149 5.6 %
Rwork0.2584 2511 -
all0.2613 2660 -
obs--99.24 %

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