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- PDB-5w5o: Identification of potent and selective RIPK2 inhibitors for the t... -

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Basic information

Entry
Database: PDB / ID: 5w5o
TitleIdentification of potent and selective RIPK2 inhibitors for the treatment of inflammatory diseases.
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTransferase/Transferase Inhibitor / Inhibitor / Kinase / Tetartohedral winning / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / LIM domain binding / positive regulation of xenophagy / CD4-positive, alpha-beta T cell proliferation / xenophagy ...response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / LIM domain binding / positive regulation of xenophagy / CD4-positive, alpha-beta T cell proliferation / xenophagy / nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of protein K63-linked ubiquitination / cellular response to muramyl dipeptide / caspase binding / positive regulation of immature T cell proliferation in thymus / CARD domain binding / JUN kinase kinase kinase activity / positive regulation of CD4-positive, alpha-beta T cell proliferation / cellular response to peptidoglycan / response to interleukin-12 / activation of cysteine-type endopeptidase activity / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of macrophage cytokine production / toll-like receptor 4 signaling pathway / response to exogenous dsRNA / positive regulation of interferon-alpha production / cellular response to lipoteichoic acid / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / ERK1 and ERK2 cascade / p75NTR recruits signalling complexes / positive regulation of interleukin-2 production / positive regulation of interferon-beta production / positive regulation of interleukin-12 production / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein ubiquitination / positive regulation of interleukin-1 beta production / activated TAK1 mediates p38 MAPK activation / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / TAK1-dependent IKK and NF-kappa-B activation / NOD1/2 Signaling Pathway / non-membrane spanning protein tyrosine kinase activity / protein homooligomerization / positive regulation of interleukin-6 production / Interleukin-1 signaling / cytokine-mediated signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / Ovarian tumor domain proteases / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / Downstream TCR signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of NF-kappaB transcription factor activity / positive regulation of protein binding / T cell receptor signaling pathway / positive regulation of canonical NF-kappaB signal transduction / vesicle / adaptive immune response / positive regulation of ERK1 and ERK2 cascade / cytoskeleton / non-specific serine/threonine protein kinase / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / positive regulation of apoptotic process / phosphorylation / signaling receptor binding / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment 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 ...Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment 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-9XA / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.89 Å
AuthorsKreusch, A. / Spraggon, G.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases.
Authors: He, X. / Da Ros, S. / Nelson, J. / Zhu, X. / Jiang, T. / Okram, B. / Jiang, S. / Michellys, P.Y. / Iskandar, M. / Espinola, S. / Jia, Y. / Bursulaya, B. / Kreusch, A. / Gao, M.Y. / Spraggon, ...Authors: He, X. / Da Ros, S. / Nelson, J. / Zhu, X. / Jiang, T. / Okram, B. / Jiang, S. / Michellys, P.Y. / Iskandar, M. / Espinola, S. / Jia, Y. / Bursulaya, B. / Kreusch, A. / Gao, M.Y. / Spraggon, G. / Baaten, J. / Clemmer, L. / Meeusen, S. / Huang, D. / Hill, R. / Nguyen-Tran, V. / Fathman, J. / Liu, B. / Tuntland, T. / Gordon, P. / Hollenbeck, T. / Ng, K. / Shi, J. / Bordone, L. / Liu, H.
History
DepositionJun 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Receptor-interacting serine/threonine-protein kinase 2
B: Receptor-interacting serine/threonine-protein kinase 2
C: Receptor-interacting serine/threonine-protein kinase 2
D: Receptor-interacting serine/threonine-protein kinase 2
E: Receptor-interacting serine/threonine-protein kinase 2
F: Receptor-interacting serine/threonine-protein kinase 2
G: Receptor-interacting serine/threonine-protein kinase 2
H: Receptor-interacting serine/threonine-protein kinase 2
I: Receptor-interacting serine/threonine-protein kinase 2
J: Receptor-interacting serine/threonine-protein kinase 2
K: Receptor-interacting serine/threonine-protein kinase 2
L: Receptor-interacting serine/threonine-protein kinase 2
M: Receptor-interacting serine/threonine-protein kinase 2
N: Receptor-interacting serine/threonine-protein kinase 2
O: Receptor-interacting serine/threonine-protein kinase 2
P: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)578,09532
Polymers569,98316
Non-polymers8,11316
Water5,477304
1
A: Receptor-interacting serine/threonine-protein kinase 2
B: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3490 Å2
ΔGint-26 kcal/mol
Surface area23600 Å2
MethodPISA
2
C: Receptor-interacting serine/threonine-protein kinase 2
D: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3610 Å2
ΔGint-28 kcal/mol
Surface area23880 Å2
MethodPISA
3
E: Receptor-interacting serine/threonine-protein kinase 2
F: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-23 kcal/mol
Surface area23950 Å2
MethodPISA
4
G: Receptor-interacting serine/threonine-protein kinase 2
H: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3570 Å2
ΔGint-27 kcal/mol
Surface area23970 Å2
MethodPISA
5
I: Receptor-interacting serine/threonine-protein kinase 2
J: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3480 Å2
ΔGint-25 kcal/mol
Surface area24090 Å2
MethodPISA
6
K: Receptor-interacting serine/threonine-protein kinase 2
L: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint-28 kcal/mol
Surface area23840 Å2
MethodPISA
7
M: Receptor-interacting serine/threonine-protein kinase 2
N: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3530 Å2
ΔGint-25 kcal/mol
Surface area23930 Å2
MethodPISA
8
O: Receptor-interacting serine/threonine-protein kinase 2
P: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2624
Polymers71,2482
Non-polymers1,0142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3670 Å2
ΔGint-26 kcal/mol
Surface area24090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.308, 107.475, 210.193
Angle α, β, γ (deg.)90.15, 89.77, 89.96
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Receptor-interacting serine/threonine-protein kinase 2 / CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ...CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ICE-kinase / RIP-like-interacting CLARP kinase / Receptor-interacting protein 2 / RIP-2 / Tyrosine-protein kinase RIPK2


Mass: 35623.910 Da / Num. of mol.: 16 / Fragment: UNP residues 2-311
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: unidentified baculovirus / Strain (production host): sf9
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-9XA / 4-{6-(tert-butylsulfonyl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl}-6-chloropyridin-2-amine


Mass: 507.049 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C23H31ClN6O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 304 / 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: 3.18 Å3/Da / Density % sol: 61.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 1.0M lithium chloride, 10.0% polyethylene glycol 6000, 0.1M TRIS pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 29, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.89→48 Å / Num. obs: 138963 / % possible obs: 89 % / Redundancy: 2.1 % / Biso Wilson estimate: 83.03 Å2 / CC1/2: 0.238 / Rmerge(I) obs: 0.11 / Net I/σ(I): 6.3
Reflection shellResolution: 2.89→3 Å / Redundancy: 1.9 % / Num. unique obs: 10631 / % possible all: 76

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished structure

Resolution: 2.89→47.9 Å / Cor.coef. Fo:Fc: 0.8976 / Cor.coef. Fo:Fc free: 0.8591 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.626 / SU Rfree Blow DPI: 0.365
RfactorNum. reflection% reflectionSelection details
Rfree0.2522 6905 4.97 %RANDOM
Rwork0.2174 ---
obs0.2191 132160 88.36 %-
Displacement parametersBiso mean: 84.8 Å2
Baniso -1Baniso -2Baniso -3
1--13.1043 Å23.6724 Å2-4.8853 Å2
2---3.1938 Å20.307 Å2
3---16.2981 Å2
Refine analyzeLuzzati coordinate error obs: 0.415 Å
Refinement stepCycle: 1 / Resolution: 2.89→47.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms34833 0 544 304 35681
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0136381HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1249782HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d11825SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes744HARMONIC2
X-RAY DIFFRACTIONt_gen_planes5233HARMONIC5
X-RAY DIFFRACTIONt_it36381HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.4
X-RAY DIFFRACTIONt_other_torsion21.49
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion4792SEMIHARMONIC5
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_contact41668SEMIHARMONIC4
LS refinement shellResolution: 2.89→2.96 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2241 282 4.68 %
Rwork0.2044 5739 -
all0.2053 6021 -
obs--88.36 %

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