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- PDB-7amg: IL-17A in complex with small molecule modulators -

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Basic information

Entry
Database: PDB / ID: 7amg
TitleIL-17A in complex with small molecule modulators
ComponentsInterleukin-17A
KeywordsIMMUNE SYSTEM / interleukin IL-17A inhibitor receptor
Function / homology
Function and homology information


positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / cell death / interleukin-17A-mediated signaling pathway / negative regulation of inflammatory response to wounding / intestinal epithelial structure maintenance / positive regulation of interleukin-23 production / positive regulation of chemokine (C-X-C motif) ligand 1 production ...positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / cell death / interleukin-17A-mediated signaling pathway / negative regulation of inflammatory response to wounding / intestinal epithelial structure maintenance / positive regulation of interleukin-23 production / positive regulation of chemokine (C-X-C motif) ligand 1 production / interleukin-17-mediated signaling pathway / positive regulation of bicellular tight junction assembly / fibroblast activation / positive regulation of cytokine production involved in inflammatory response / positive regulation of osteoclast differentiation / keratinocyte proliferation / cellular response to interleukin-1 / defense response to fungus / keratinocyte differentiation / Notch signaling pathway / positive regulation of interleukin-12 production / positive regulation of interleukin-1 beta production / cytokine activity / response to wounding / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / cell-cell signaling / gene expression / Interleukin-4 and Interleukin-13 signaling / defense response to Gram-negative bacterium / adaptive immune response / defense response to Gram-positive bacterium / inflammatory response / immune response / protein heterodimerization activity / external side of plasma membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region
Similarity search - Function
Interleukin-17, chordata / Interleukin-17 family / Interleukin-17 / Cystine-knot cytokine
Similarity search - Domain/homology
Chem-RMQ / Interleukin-17A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.18 Å
AuthorsHakansson, M. / Kimbung, R. / Logan, D. / Walse, U.B. / de Groot, M.J. / Andrews, M.D. / Dack, K.N. / Lambert, M.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.
Authors: Andrews, M.D. / Dack, K.N. / de Groot, M.J. / Lambert, M. / Sennbro, C.J. / Larsen, M. / Stahlhut, M.
History
DepositionOct 8, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-17A
B: Interleukin-17A
C: Interleukin-17A
D: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,2906
Polymers50,6294
Non-polymers1,6612
Water18010
1
A: Interleukin-17A
B: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,1453
Polymers25,3152
Non-polymers8301
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5150 Å2
ΔGint-28 kcal/mol
Surface area12240 Å2
MethodPISA
2
C: Interleukin-17A
D: Interleukin-17A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,1453
Polymers25,3152
Non-polymers8301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-26 kcal/mol
Surface area11990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)165.006, 119.043, 54.290
Angle α, β, γ (deg.)90.00, 90.54, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: _ / Auth seq-ID: 19 - 127 / Label seq-ID: 1 - 109

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Interleukin-17A / IL-17A / Cytotoxic T-lymphocyte-associated antigen 8 / CTLA-8


Mass: 12657.340 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL17A, CTLA8, IL17
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q16552
#2: Chemical ChemComp-RMQ / (3~{R})-4-[4-[[(2~{S})-2-[[2,2-bis(fluoranyl)-2-phenyl-ethanoyl]amino]-3-(2-chlorophenyl)propanoyl]amino]phenyl]-3-[[(2~{S})-3-methyl-2-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethanoylamino]butanoyl]amino]butanoic acid


Mass: 830.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H50ClF2N5O9 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 5.63 Å3/Da / Density % sol: 78.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 10000, isopropanol, sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 3.18→28.87 Å / Num. obs: 17232 / % possible obs: 97.8 % / Redundancy: 2.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.098 / Net I/σ(I): 9.2
Reflection shellResolution: 3.18→3.4 Å / Rmerge(I) obs: 1.184 / Num. unique obs: 2973 / CC1/2: 0.338

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HR9

4hr9


Resolution: 3.18→28.86 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.928 / SU B: 37.808 / SU ML: 0.286 / Cross valid method: THROUGHOUT / ESU R: 0.762 / ESU R Free: 0.34 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22704 795 4.6 %RANDOM
Rwork0.20351 ---
obs0.20461 16355 97.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 108.108 Å2
Baniso -1Baniso -2Baniso -3
1-0.95 Å20 Å2-0.47 Å2
2--1.3 Å20 Å2
3----2.24 Å2
Refinement stepCycle: 1 / Resolution: 3.18→28.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3309 0 116 10 3435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193522
X-RAY DIFFRACTIONr_bond_other_d0.0070.023356
X-RAY DIFFRACTIONr_angle_refined_deg2.0421.9744801
X-RAY DIFFRACTIONr_angle_other_deg1.5963.0057584
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.5675399
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.58222.989174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.06315555
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7721537
X-RAY DIFFRACTIONr_chiral_restr0.1130.2509
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213944
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02873
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_it7.5038.1381620
X-RAY DIFFRACTIONr_mcbond_other7.4878.1391619
X-RAY DIFFRACTIONr_mcangle_it11.49412.182011
X-RAY DIFFRACTIONr_mcangle_other11.49312.1822012
X-RAY DIFFRACTIONr_scbond_it7.869.0951902
X-RAY DIFFRACTIONr_scbond_other7.8589.0951903
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.04413.3652791
X-RAY DIFFRACTIONr_long_range_B_refined17.14678.72813304
X-RAY DIFFRACTIONr_long_range_B_other17.14778.72813303
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A50700.17
12B50700.17
21A51070.16
22C51070.16
31A51390.17
32D51390.17
41B53590.13
42C53590.13
51B51630.16
52D51630.16
61C50960.17
62D50960.17
LS refinement shellResolution: 3.184→3.265 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.415 47 -
Rwork0.362 961 -
obs--80.64 %
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)
12.73183.11850.94275.20043.2233.2118-0.13870.13620.3284-0.1312-0.07240.45910.0176-0.36590.21110.24440.0163-0.05980.25550.06780.176-18.141-14.6483.658
23.6926-3.85171.68875.382-2.68692.1559-0.0913-0.40230.00460.19830.29380.1558-0.1621-0.2199-0.20240.09950.12570.04010.23970.04640.0921-36.8427.90124.939
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A19 - 500
2X-RAY DIFFRACTION1B19 - 127
3X-RAY DIFFRACTION2C19 - 127
4X-RAY DIFFRACTION2D19 - 500

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