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- PDB-4neu: X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase do... -

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Basic information

Entry
Database: PDB / ID: 4neu
TitleX-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor
ComponentsReceptor-interacting serine/threonine-protein kinase 1
KeywordsTRANSFERASE / Kinase / ATP binding / Phosphorylation
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 / SARS-CoV-1-mediated effects on programmed cell death / positive regulation of macrophage differentiation / 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 / 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 / TRP channels / 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 / extrinsic apoptotic signaling pathway / negative regulation of canonical NF-kappaB signal transduction / 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 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 tumor necrosis factor production / positive regulation of reactive oxygen species metabolic process / positive regulation of neuron apoptotic process / 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 / 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 / positive regulation of gene expression / protein-containing complex binding / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-Q1A / Receptor-interacting serine/threonine-protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsNolte, R.T. / Ward, P. / kahler, K.M. / Campobasso, N.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis.
Authors: Harris, P.A. / Bandyopadhyay, D. / Berger, S.B. / Campobasso, N. / Capriotti, C.A. / Cox, J.A. / Dare, L. / Finger, J.N. / Hoffman, S.J. / Kahler, K.M. / Lehr, R. / Lich, J.D. / Nagilla, R. ...Authors: Harris, P.A. / Bandyopadhyay, D. / Berger, S.B. / Campobasso, N. / Capriotti, C.A. / Cox, J.A. / Dare, L. / Finger, J.N. / Hoffman, S.J. / Kahler, K.M. / Lehr, R. / Lich, J.D. / Nagilla, R. / Nolte, R.T. / Ouellette, M.T. / Pao, C.S. / Schaeffer, M.C. / Smallwood, A. / Sun, H.H. / Swift, B.A. / Totoritis, R.D. / Ward, P. / Marquis, R.W. / Bertin, J. / Gough, P.J.
History
DepositionOct 30, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)77,2455
Polymers76,4182
Non-polymers8273
Water4,270237
1
A: Receptor-interacting serine/threonine-protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6353
Polymers38,2091
Non-polymers4262
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)38,6102
Polymers38,2091
Non-polymers4011
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)149.249, 149.249, 187.670
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.444714, -0.681609, 0.581067), (-0.706265, -0.132116, -0.69551), (0.550835, -0.71969, -0.422643)87.86397, 131.1768, 74.78335

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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: 38209.016 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-Q1A / 1-[4-(1-aminoisoquinolin-5-yl)phenyl]-3-(5-tert-butyl-1,2-oxazol-3-yl)urea


Mass: 401.461 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.63 Å3/Da / Density % sol: 53.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M Potasium Chloride, 0.05 BisTris, pH=6.5, 40 % v/v pentaerythritol propoxylate (5/4 PO/OH) Crystals were looped and plunged into liquid nitrogen, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 26, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.57→106.5 Å / Num. all: 25792 / Num. obs: 25792 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.57→47.94 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.921 / SU B: 15.807 / SU ML: 0.187 / Cross valid method: THROUGHOUT / ESU R: 0.407 / ESU R Free: 0.265 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23537 822 3.2 %RANDOM
Rwork0.1808 ---
all0.18254 25792 --
obs0.1808 24724 99.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 54.904 Å2
Baniso -1Baniso -2Baniso -3
1--0.81 Å2-0.41 Å20 Å2
2---0.81 Å20 Å2
3---1.22 Å2
Refinement stepCycle: LAST / Resolution: 2.57→47.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4323 0 61 237 4621
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194482
X-RAY DIFFRACTIONr_bond_other_d0.0010.023037
X-RAY DIFFRACTIONr_angle_refined_deg1.281.9726054
X-RAY DIFFRACTIONr_angle_other_deg0.87637449
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9145551
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.12324.811185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.92615811
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.321518
X-RAY DIFFRACTIONr_chiral_restr0.0730.2667
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214898
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02858
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.57→2.637 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 60 -
Rwork0.242 1717 -
obs--100 %
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)
13.2821-1.32941.59024.6068-2.56473.4021-0.1452-0.063-0.36150.20070.21920.4110.3776-0.4563-0.0740.4422-0.07950.03950.28760.07690.147123.32653.35855.295
23.79664.4012-2.152210.7765-0.98246.0055-0.02610.069-0.5185-0.0259-0.00520.23220.6681-0.58810.03130.3871-0.0491-0.0010.31140.07070.265425.10454.87747.671
34.1544-0.9987-0.42332.8175-0.22072.9537-0.0021-0.24520.0290.24560.0657-0.05790.25220.0788-0.06360.238-0.00810.02240.09180.00440.010338.02468.21648.79
41.0931.48970.45044.41470.10272.02180.1051-0.57450.240.2047-0.25291.1796-0.0227-0.84220.14790.391-0.0410.06690.6164-0.05260.433323.55875.65852.433
51.6345-0.5497-0.88131.75471.46793.39540.0957-0.11040.2353-0.11160.0941-0.2817-0.14720.1674-0.18990.2074-0.0420.04570.1073-0.00630.070140.42279.96548.614
69.1652-0.0902-1.27965.9504-0.50396.6-0.0270.37360.6752-0.24640.177-1.4759-0.41262.0055-0.150.3701-0.09310.03640.9595-0.13880.633369.47269.47224.562
71.9911-0.0228-0.89861.44080.05374.7169-0.10470.1732-0.0336-0.00690.1169-0.03280.5523-0.1099-0.01210.2181-0.0250.03670.0560.0030.033146.80660.26819.665
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 69
2X-RAY DIFFRACTION2A70 - 92
3X-RAY DIFFRACTION3A93 - 151
4X-RAY DIFFRACTION4A152 - 206
5X-RAY DIFFRACTION5A207 - 324
6X-RAY DIFFRACTION6B1 - 92
7X-RAY DIFFRACTION7B93 - 324

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