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- PDB-5hi5: Binding site elucidation and structure guided design of macrocycl... -

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Basic information

Entry
Database: PDB / ID: 5hi5
TitleBinding site elucidation and structure guided design of macrocyclic IL-17A antagonists
Components
  • CAT-2000 FAB heavy chain
  • CAT-2000 light chain
  • Interleukin-17A
  • synthetic IL-17A 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 / interleukin-17A-mediated signaling pathway / cell death / 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 / interleukin-17A-mediated signaling pathway / cell death / 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 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 / 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 Cytokines, subunit B / Cystine-knot cytokines / Cystine-knot cytokine / Ribbon / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-63Q / Interleukin-17A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / 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 1.2Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 light chain
H: CAT-2000 FAB heavy chain
I: synthetic IL-17A inhibitor
L: CAT-2000 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,8758
Polymers128,2627
Non-polymers6131
Water5,747319
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.320, 68.680, 100.530
Angle α, β, γ (deg.)90.00, 90.65, 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) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Antibody CAT-2000 light chain


Mass: 23006.342 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / 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 / Plasmid: pPpARG4 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16552
#4: Protein/peptide synthetic IL-17A 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, 320 molecules

#5: Chemical ChemComp-63Q / (4S,20R)-7-chloro-N-methyl-4-{[(1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-3,18-dioxo-2,19-diazatetracyclo[20.2.2.1~6,10~.1~11,15~]octacosa-1(24),6(28),7,9,11(27),12,14,22,25-nonaene-20-carboxamide


Mass: 613.106 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H33ClN6O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 319 / 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: 2.46 Å3/Da / Density % sol: 49.95 %
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

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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: Sep 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→91.31 Å / Num. obs: 113034 / % possible obs: 97.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 33.38 Å2 / Rmerge(I) obs: 0.037 / Net I/σ(I): 19.9
Reflection shellResolution: 1.8→2.08 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.408 / Mean I/σ(I) obs: 4.6 / % possible all: 97.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
autoPROCdata scaling
Aimlessdata scaling
PHASERphasing
RefinementResolution: 1.8→91.31 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.9467 / SU R Cruickshank DPI: 0.121 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.118 / SU Rfree Blow DPI: 0.108 / SU Rfree Cruickshank DPI: 0.11
RfactorNum. reflection% reflectionSelection details
Rfree0.2191 5555 5.02 %RANDOM
Rwork0.2007 ---
obs0.2016 110571 95.79 %-
Displacement parametersBiso mean: 47.82 Å2
Baniso -1Baniso -2Baniso -3
1--1.0923 Å20 Å2-1.9018 Å2
2---2.3326 Å20 Å2
3---3.4248 Å2
Refine analyzeLuzzati coordinate error obs: 0.259 Å
Refinement stepCycle: 1 / Resolution: 1.8→91.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8040 0 44 319 8403
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018328HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0811394HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2711SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes163HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1258HARMONIC5
X-RAY DIFFRACTIONt_it8328HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.7
X-RAY DIFFRACTIONt_other_torsion17.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1105SEMIHARMONIC5
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_contact8988SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3028 398 5.21 %
Rwork0.2676 7239 -
all0.2694 7637 -
obs--89.63 %
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)
10.6130.3765-0.3250.8434-0.32724.4690.01570.036-0.19590.13660.0172-0.21390.40740.5821-0.03280.05940.00530.0803-0.0401-0.0884-0.078774.3911-30.8624-42.3863
21.38690.3469-0.37271.50310.31563.6372-0.07440.3946-0.4962-0.20970.0719-0.26210.9610.06290.00260.1188-0.01870.0948-0.1043-0.1636-0.110566.5804-39.0838-49.2691
30.84270.2789-0.51290.7297-0.5150.69670.008-0.17940.06960.1331-0.0661-0.0131-0.0585-0.03290.0582-0.0549-0.02970.0095-0.0482-0.0364-0.009181.8338-23.4446-84.9169
40.9450.9678-0.6781.1705-1.59221.91880.2834-0.11830.31350.3340.04620.3672-0.3584-0.1553-0.3296-0.08380.01720.0956-0.1916-0.0601-0.015475.7568-7.1456-87.9848
50.9510.0289-0.82460.5683-0.18650.7979-0.0358-0.0073-0.0858-0.1578-0.01030.07090.04030.05240.0461-0.0981-0.0146-0.011-0.0555-0.0211-0.000450.5398-30.0499-8.1449
6-0.0258-1.48211.1391.22750.9790.0349-0.0019-0.1141-0.0817-0.0265-0.0255-0.03620.03540.07350.02740.1330.17080.0008-0.23170.01130.035976.8378-60.7559-40.1141
70.5433-0.0006-0.53350.4127-0.08921.32040.02950.06020.0001-0.01190.0209-0.0275-0.1337-0.1069-0.0505-0.0740.01040.0082-0.05890.0057-0.023640.8842-15.5391-9.6956
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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