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- PDB-6r5f: Crystal structure of RIP1 kinase in complex with DHP77 -

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Basic information

Entry
Database: PDB / ID: 6r5f
TitleCrystal structure of RIP1 kinase in complex with DHP77
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 interleukin-6-mediated signaling pathway / positive regulation of miRNA processing / 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 interleukin-6-mediated signaling pathway / positive regulation of miRNA processing / 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 / programmed necrotic cell death / TNF signaling / Caspase activation via Death Receptors in the presence of ligand / T cell apoptotic process / positive regulation of macrophage differentiation / SARS-CoV-1-mediated effects on programmed cell death / necroptotic signaling pathway / JUN kinase kinase kinase activity / peptidyl-serine autophosphorylation / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / positive regulation of necroptotic process / death-inducing signaling complex / RIP-mediated NFkB activation via ZBP1 / negative regulation of necroptotic process / positive regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / TRP channels / positive regulation of extrinsic apoptotic signaling pathway / positive regulation of programmed cell death / positive regulation of programmed necrotic cell death / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / positive regulation of execution phase of apoptosis / necroptotic process / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / response to tumor necrosis factor / signaling adaptor activity / negative regulation of canonical NF-kappaB signal transduction / extrinsic apoptotic signaling pathway / tumor necrosis factor-mediated 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 / Regulation of TNFR1 signaling / positive regulation of JNK cascade / protein catabolic process / Regulation of necroptotic cell death / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / 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 / Ovarian tumor domain proteases / positive regulation of tumor necrosis factor production / 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 / endosome membrane / non-specific serine/threonine protein kinase / Ub-specific processing proteases / protein kinase activity / intracellular signal transduction / inflammatory response / positive regulation of protein phosphorylation / positive regulation of apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / ubiquitin protein ligase binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-JSW / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.25 Å
AuthorsThorpe, J.H. / Campobasso, N. / Harris, P.A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.
Authors: Harris, P.A. / Faucher, N. / George, N. / Eidam, P.M. / King, B.W. / White, G.V. / Anderson, N.A. / Bandyopadhyay, D. / Beal, A.M. / Beneton, V. / Berger, S.B. / Campobasso, N. / Campos, S. ...Authors: Harris, P.A. / Faucher, N. / George, N. / Eidam, P.M. / King, B.W. / White, G.V. / Anderson, N.A. / Bandyopadhyay, D. / Beal, A.M. / Beneton, V. / Berger, S.B. / Campobasso, N. / Campos, S. / Capriotti, C.A. / Cox, J.A. / Daugan, A. / Donche, F. / Fouchet, M.H. / Finger, J.N. / Geddes, B. / Gough, P.J. / Grondin, P. / Hoffman, B.L. / Hoffman, S.J. / Hutchinson, S.E. / Jeong, J.U. / Jigorel, E. / Lamoureux, P. / Leister, L.K. / Lich, J.D. / Mahajan, M.K. / Meslamani, J. / Mosley, J.E. / Nagilla, R. / Nassau, P.M. / Ng, S.L. / Ouellette, M.T. / Pasikanti, K.K. / Potvain, F. / Reilly, M.A. / Rivera, E.J. / Sautet, S. / Schaeffer, M.C. / Sehon, C.A. / Sun, H. / Thorpe, J.H. / Totoritis, R.D. / Ward, P. / Wellaway, N. / Wisnoski, D.D. / Woolven, J.M. / Bertin, J. / Marquis, R.W.
History
DepositionMar 25, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 21, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Jan 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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
C: Receptor-interacting serine/threonine-protein kinase 1
D: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,8978
Polymers138,3884
Non-polymers1,5104
Water0
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9742
Polymers34,5971
Non-polymers3771
Water0
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)34,9742
Polymers34,5971
Non-polymers3771
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9742
Polymers34,5971
Non-polymers3771
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9742
Polymers34,5971
Non-polymers3771
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.858, 138.919, 96.534
Angle α, β, γ (deg.)90.00, 96.50, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 4
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-JSW / [(5~{S})-5-[3,5-bis(fluoranyl)phenyl]pyrazolidin-1-yl]-[1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl]methanone / DHP77


Mass: 377.388 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H21F2N5O2 / Feature type: SUBJECT OF INVESTIGATION

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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: 44.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.2M Ammonium Fluoride, 20% PEG3350 and 4mM DHP77

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3.25→69.46 Å / Num. obs: 18831 / % possible obs: 99.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 88.89 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.137 / Rpim(I) all: 0.089 / Rrim(I) all: 0.164 / Net I/σ(I): 9.3
Reflection shellResolution: 3.25→3.98 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.453 / Num. unique obs: 8493 / CC1/2: 0.772 / Rpim(I) all: 0.297 / Rrim(I) all: 0.543 / % possible all: 98.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ITJ

4itj


Resolution: 3.25→69.46 Å / Cor.coef. Fo:Fc: 0.864 / Cor.coef. Fo:Fc free: 0.795 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.595
RfactorNum. reflection% reflectionSelection details
Rfree0.289 926 4.93 %RANDOM
Rwork0.243 ---
obs0.245 18790 99.1 %-
Displacement parametersBiso mean: 85.7 Å2
Baniso -1Baniso -2Baniso -3
1--15.4685 Å20 Å25.6557 Å2
2--7.0639 Å20 Å2
3---8.4046 Å2
Refine analyzeLuzzati coordinate error obs: 0.56 Å
Refinement stepCycle: 1 / Resolution: 3.25→69.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8122 0 108 0 8230
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018402HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1311318HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3021SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes208HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1165HARMONIC5
X-RAY DIFFRACTIONt_it8402HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.49
X-RAY DIFFRACTIONt_other_torsion18.62
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1076SEMIHARMONIC5
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_contact9211SEMIHARMONIC4
LS refinement shellResolution: 3.25→3.45 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.289 147 4.87 %
Rwork0.244 2869 -
all0.246 3016 -
obs--98.69 %

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