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- PDB-5hi4: Binding site elucidation and structure guided design of macrocycl... -

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Basic information

Entry
Database: PDB / ID: 5hi4
TitleBinding site elucidation and structure guided design of macrocyclic IL-17A antagonists
Components
  • (CAT-2000 FAB ...) x 2
  • Interleukin-17A
  • synthetic IL-17A peptide inhibitor
KeywordsIMMUNE SYSTEM/INHIBITOR / IL-17A / psoriasis / MD simulation / sulfonyl fluoride / inhibitor / macrocycle / IMMUNE SYSTEM-INHIBITOR complex
Function / homology
Function and homology information


positive regulation of interleukin-16 production / granulocyte migration / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / cell death / 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 / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / cell death / 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 osteoclast differentiation / positive regulation of cytokine production involved in inflammatory response / 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 / adaptive immune response / defense response to Gram-negative bacterium / 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 Cytokines, subunit B / Cystine-knot cytokines / Cystine-knot cytokine / Ribbon / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-63P / Interleukin-17A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsLiu, S.
CitationJournal: Sci Rep / Year: 2016
Title: Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists.
Authors: Liu, S. / Dakin, L.A. / Xing, L. / Withka, J.M. / Sahasrabudhe, P.V. / Li, W. / Banker, M.E. / Balbo, P. / Shanker, S. / Chrunyk, B.A. / Guo, Z. / Chen, J.M. / Young, J.A. / Bai, G. / Starr, ...Authors: Liu, S. / Dakin, L.A. / Xing, L. / Withka, J.M. / Sahasrabudhe, P.V. / Li, W. / Banker, M.E. / Balbo, P. / Shanker, S. / Chrunyk, B.A. / Guo, Z. / Chen, J.M. / Young, J.A. / Bai, G. / Starr, J.T. / Wright, S.W. / Bussenius, J. / Tan, S. / Gopalsamy, A. / Lefker, B.A. / Vincent, F. / Jones, L.H. / Xu, H. / Hoth, L.R. / Geoghegan, K.F. / Qiu, X. / Bunnage, M.E. / Thorarensen, A.
History
DepositionJan 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.2Sep 27, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Interleukin-17A
B: Interleukin-17A
C: CAT-2000 FAB heavy chain
D: CAT-2000 FAB light chain
H: CAT-2000 FAB heavy chain
I: synthetic IL-17A peptide inhibitor
L: CAT-2000 FAB light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,9458
Polymers128,2627
Non-polymers6831
Water5,837324
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.240, 68.190, 100.120
Angle α, β, γ (deg.)90.00, 91.33, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Antibody , 2 types, 4 molecules CHDL

#2: Antibody CAT-2000 FAB heavy chain


Mass: 25053.898 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody CAT-2000 FAB light chain


Mass: 23006.342 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Protein/peptide , 2 types, 3 molecules ABI

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


Mass: 15146.124 Da / Num. of mol.: 2 / Fragment: UNP residues 24-155
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL17A, CTLA8, IL17 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16552
#4: Protein/peptide synthetic IL-17A peptide inhibitor


Mass: 1849.136 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 325 molecules

#5: Chemical ChemComp-63P / (9'S,17'R)-6'-chloro-N-methyl-9'-{[(1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-10',19'-dioxo-2'-oxa-11',18'-diazaspiro[cyclopentane-1,21'-tetracyclo[20.2.2.2~12,15~.1~3,7~]nonacosane]-1'(24'),3'(29'),4',6',12',14',22',25',27'-nonaene-17'-carboxamide


Mass: 683.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H39ClN6O5
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 324 / 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: 2.43 Å3/Da / Density % sol: 49.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 10% 2-propanol, 20-24% PEG 6K, 0.1 M sodium acetate pH=4.0-5.0
PH range: 4-5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 17, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50.5 Å / Num. obs: 97577 / % possible obs: 99.1 % / Redundancy: 2.8 % / Biso Wilson estimate: 25.36 Å2 / Rmerge(I) obs: 0.056 / Net I/σ(I): 169.6
Reflection shellResolution: 1.8→1.97 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.75 / % possible all: 99.6

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
autoPROCdata scaling
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2VXS

2vxs


Resolution: 1.8→50.05 Å / Cor.coef. Fo:Fc: 0.9418 / Cor.coef. Fo:Fc free: 0.9334 / SU R Cruickshank DPI: 0.137 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.134 / SU Rfree Blow DPI: 0.122 / SU Rfree Cruickshank DPI: 0.124
RfactorNum. reflection% reflectionSelection details
Rfree0.2238 4869 4.99 %RANDOM
Rwork0.1995 ---
obs0.2008 97577 85.57 %-
Displacement parametersBiso mean: 37.78 Å2
Baniso -1Baniso -2Baniso -3
1-3.0211 Å20 Å2-1.8609 Å2
2---0.7284 Å20 Å2
3----2.2927 Å2
Refine analyzeLuzzati coordinate error obs: 0.266 Å
Refinement stepCycle: 1 / Resolution: 1.8→50.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8049 0 49 324 8422
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018355HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1211444HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2714SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes163HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1263HARMONIC5
X-RAY DIFFRACTIONt_it8355HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.8
X-RAY DIFFRACTIONt_other_torsion16.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1104SEMIHARMONIC5
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_contact9094SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3145 263 4.91 %
Rwork0.3032 5093 -
all0.3038 5356 -
obs--64.03 %
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)
11.9030.377-0.7461.5904-0.14863.4419-0.0379-0.0024-0.4075-0.0619-0.0118-0.51040.47240.53150.04970.20420.05380.04460.0879-0.05160.106675.7101-32.3518-41.2066
20.93530.1587-0.27110.7664-0.53712.9504-0.04940.163-0.3869-0.15580.0119-0.09530.8269-0.04640.03750.4386-0.0480.09280.0047-0.10020.099267.5339-41.1507-49.7367
30.65650.294-0.39330.7568-0.35840.5436-0.0081-0.10280.05410.1362-0.0549-0.0032-0.0238-0.03150.0630.1724-0.027-0.00530.0829-0.03230.080382.2567-23.5256-84.6421
40.91550.8594-0.96550.8126-1.49072.43590.2439-0.01860.24670.28660.06110.2774-0.3574-0.227-0.30510.22870.01850.0670.036-0.05090.131576.2361-7.1869-87.6717
50.80270.0096-0.70260.5411-0.07330.6361-0.0056-0.0275-0.101-0.1109-0.02570.0579-0.00160.0270.03130.123-0.0178-0.03160.0607-0.0160.068750.6551-30.0631-8.0737
60.0913-0.5201-2.0045.09351.00643.34120.001-0.1497-0.1197-0.0017-0.0268-0.09690.03730.13310.02580.36220.28580.0601-0.06650.11840.298876.8385-60.6802-40.0566
70.4963-0.0275-0.60550.3644-0.09261.40950.03560.0625-0.0164-0.01190.0212-0.0116-0.1097-0.1045-0.05680.15560.0048-0.01290.06620.00110.065841.0082-15.5429-9.6674
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ H|* }
6X-RAY DIFFRACTION6{ I|* }
7X-RAY DIFFRACTION7{ L|* }

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