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- PDB-8ryk: IL-1beta in complex with macrocyclic peptide hit -

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Basic information

Entry
Database: PDB / ID: 8ryk
TitleIL-1beta in complex with macrocyclic peptide hit
Components
  • Interleukin-1 beta
  • Macrocyclic peptide
KeywordsCYTOKINE / Peptide Discovery Platform
Function / homology
Function and homology information


positive regulation of T cell mediated immunity / positive regulation of cell adhesion molecule production / negative regulation of adiponectin secretion / monocyte aggregation / negative regulation of lipid metabolic process / smooth muscle adaptation / positive regulation of lipid catabolic process / negative regulation of D-glucose transmembrane transport / regulation of nitric-oxide synthase activity / hyaluronan biosynthetic process ...positive regulation of T cell mediated immunity / positive regulation of cell adhesion molecule production / negative regulation of adiponectin secretion / monocyte aggregation / negative regulation of lipid metabolic process / smooth muscle adaptation / positive regulation of lipid catabolic process / negative regulation of D-glucose transmembrane transport / regulation of nitric-oxide synthase activity / hyaluronan biosynthetic process / positive regulation of T-helper 1 cell cytokine production / positive regulation of complement activation / : / cellular response to interleukin-17 / positive regulation of RNA biosynthetic process / positive regulation of tight junction disassembly / positive regulation of prostaglandin biosynthetic process / negative regulation of gap junction assembly / positive regulation of immature T cell proliferation in thymus / vascular endothelial growth factor production / positive regulation of prostaglandin secretion / positive regulation of neuroinflammatory response / positive regulation of platelet-derived growth factor receptor signaling pathway / regulation of defense response to virus by host / fever generation / positive regulation of fever generation / regulation of establishment of endothelial barrier / CLEC7A/inflammasome pathway / Interleukin-1 processing / negative regulation of synaptic transmission / response to carbohydrate / positive regulation of monocyte chemotactic protein-1 production / interleukin-1 receptor binding / positive regulation of heterotypic cell-cell adhesion / positive regulation of macrophage derived foam cell differentiation / positive regulation of p38MAPK cascade / positive regulation of membrane protein ectodomain proteolysis / positive regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of granulocyte macrophage colony-stimulating factor production / regulation of canonical NF-kappaB signal transduction / interleukin-1-mediated signaling pathway / response to ATP / Interleukin-10 signaling / positive regulation of cell division / regulation of neurogenesis / positive regulation of vascular endothelial growth factor production / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of MAP kinase activity / Pyroptosis / ectopic germ cell programmed cell death / negative regulation of lipid catabolic process / regulation of ERK1 and ERK2 cascade / Purinergic signaling in leishmaniasis infection / positive regulation of epithelial to mesenchymal transition / positive regulation of T cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / JNK cascade / positive regulation of glial cell proliferation / neutrophil chemotaxis / embryo implantation / negative regulation of insulin receptor signaling pathway / positive regulation of interleukin-2 production / response to interleukin-1 / positive regulation of mitotic nuclear division / regulation of insulin secretion / secretory granule / positive regulation of protein export from nucleus / cytokine activity / positive regulation of interleukin-8 production / astrocyte activation / positive regulation of JNK cascade / positive regulation of non-canonical NF-kappaB signal transduction / cytokine-mediated signaling pathway / negative regulation of neurogenesis / positive regulation of interleukin-6 production / positive regulation of type II interferon production / Interleukin-1 signaling / cellular response to mechanical stimulus / positive regulation of inflammatory response / positive regulation of angiogenesis / positive regulation of NF-kappaB transcription factor activity / positive regulation of nitric oxide biosynthetic process / integrin binding / cellular response to xenobiotic stimulus / cell-cell signaling / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / response to lipopolysaccharide / positive regulation of canonical NF-kappaB signal transduction / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / defense response to Gram-positive bacterium / immune response / positive regulation of cell migration / inflammatory response / protein domain specific binding / negative regulation of cell population proliferation / apoptotic process
Similarity search - Function
Interleukin-1 propeptide / Interleukin-1 propeptide / Interleukin-1 conserved site / Interleukin-1 signature. / Interleukin-1 homologues / Interleukin-1 family / Interleukin-1 / 18 / Cytokine IL1/FGF
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsRondeau, J.-M. / Lehmann, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: J.Med.Chem. / Year: 2024
Title: Ligandability Assessment of IL-1 beta by Integrated Hit Identification Approaches.
Authors: Vulpetti, A. / Rondeau, J.M. / Bellance, M.H. / Blank, J. / Boesch, R. / Boettcher, A. / Bornancin, F. / Buhr, S. / Connor, L.E. / Dumelin, C.E. / Esser, O. / Hediger, M. / Hintermann, S. / ...Authors: Vulpetti, A. / Rondeau, J.M. / Bellance, M.H. / Blank, J. / Boesch, R. / Boettcher, A. / Bornancin, F. / Buhr, S. / Connor, L.E. / Dumelin, C.E. / Esser, O. / Hediger, M. / Hintermann, S. / Hommel, U. / Koch, E. / Lapointe, G. / Leder, L. / Lehmann, S. / Lehr, P. / Meier, P. / Muller, L. / Ostermeier, D. / Ramage, P. / Schiebel-Haddad, S. / Smith, A.B. / Stojanovic, A. / Velcicky, J. / Yamamoto, R. / Hurth, K.
#1: Journal: Nat Commun / Year: 2023
Title: Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1beta.
Authors: Hommel, U. / Hurth, K. / Rondeau, J.M. / Vulpetti, A. / Ostermeier, D. / Boettcher, A. / Brady, J.P. / Hediger, M. / Lehmann, S. / Koch, E. / Blechschmidt, A. / Yamamoto, R. / Tundo ...Authors: Hommel, U. / Hurth, K. / Rondeau, J.M. / Vulpetti, A. / Ostermeier, D. / Boettcher, A. / Brady, J.P. / Hediger, M. / Lehmann, S. / Koch, E. / Blechschmidt, A. / Yamamoto, R. / Tundo Dottorello, V. / Haenni-Holzinger, S. / Kaiser, C. / Lehr, P. / Lingel, A. / Mureddu, L. / Schleberger, C. / Blank, J. / Ramage, P. / Freuler, F. / Eder, J. / Bornancin, F.
History
DepositionFeb 9, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-1 beta
B: Interleukin-1 beta
C: Macrocyclic peptide
D: Macrocyclic peptide


Theoretical massNumber of molelcules
Total (without water)39,0124
Polymers39,0124
Non-polymers00
Water3,333185
1
A: Interleukin-1 beta
C: Macrocyclic peptide


Theoretical massNumber of molelcules
Total (without water)19,5062
Polymers19,5062
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1360 Å2
ΔGint-7 kcal/mol
Surface area9250 Å2
MethodPISA
2
B: Interleukin-1 beta
D: Macrocyclic peptide


Theoretical massNumber of molelcules
Total (without water)19,5062
Polymers19,5062
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1460 Å2
ΔGint-7 kcal/mol
Surface area9390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.777, 67.394, 80.219
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 Interleukin-1 beta / IL-1 beta / Catabolin


Mass: 17395.832 Da / Num. of mol.: 2 / Fragment: Fab light-chain
Source method: isolated from a genetically manipulated source
Details: Mature human Interleukin-1beta / Source: (gene. exp.) Homo sapiens (human) / Gene: IL1B, IL1F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01584
#2: Protein/peptide Macrocyclic peptide


Mass: 2110.266 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 185 / 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: 2.16 Å3/Da / Density % sol: 43.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.1M citrate pH 5.0, 1.6M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00004 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 1.8→51.601 Å / Num. obs: 30169 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 6.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.102 / Rrim(I) all: 0.111 / Net I/σ(I): 10.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.8-1.856.21.741.1122010.5841.90199.9
1.85-1.91.5511.3421380.6981.68899.9
1.9-1.951.0591.9620770.7851.14699.7
1.95-2.010.8492.4320330.870.919100
2.01-2.080.5973.2519570.9350.64899.8
2.08-2.150.4693.9319140.9560.509100
2.15-2.230.4314.2118420.9650.47199.5
2.23-2.320.3655.5517530.960.39799
2.32-2.430.2566.9717070.9810.278100
2.43-2.550.2247.8616280.9860.242100
2.55-2.680.16610.1415740.9920.18199.9
2.68-2.850.1312.4614700.9940.142100
2.85-3.040.09216.5713780.9970.1100
3.04-3.290.0722.0913150.9980.07699.8
3.29-3.60.05725.7312030.9980.062100
3.6-4.020.0528.0611020.9990.054100
4.02-4.650.03834.389710.9990.04199.9
4.65-5.690.03634.468400.9990.039100
5.69-8.050.03631.266700.9990.0499.9
8.05-51.6010.02538.2739610.028100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XSCALEOct. 15, 2015data scaling
XDSOct. 15, 2015data reduction
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→47.41 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.138
RfactorNum. reflection% reflectionSelection details
Rfree0.248 1509 5 %RANDOM
Rwork0.209 ---
obs0.211 30168 99.8 %-
Displacement parametersBiso mean: 41.47 Å2
Baniso -1Baniso -2Baniso -3
1-0.3147 Å20 Å20 Å2
2---2.1031 Å20 Å2
3---1.7884 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 1.8→47.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2438 0 289 185 2912
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012797HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.233778HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d952SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes471HARMONIC5
X-RAY DIFFRACTIONt_it2797HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.06
X-RAY DIFFRACTIONt_other_torsion15.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion337SEMIHARMONIC5
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_contact3135SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.81 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2563 -4.97 %
Rwork0.223 574 -
all0.2248 604 -
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)
12.4927-0.2071-0.27451.52150.57411.9364-0.1249-0.2851-0.14340.1250.12680.09940.05860.0411-0.002-0.21340.02870.00780.1240.0477-0.075322.7376-5.1545-6.1266
23.36670.89120.87131.140.08562.0681-0.13120.3819-0.0542-0.0717-0.0424-0.0412-0.04950.19080.1736-0.22490.01070.00460.14590.0276-0.049551.99865.9057-7.4989
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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