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- PDB-8gab: Crystal structure of CTLA-4 in complex with a high affinity CTLA-... -

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Basic information

Entry
Database: PDB / ID: 8gab
TitleCrystal structure of CTLA-4 in complex with a high affinity CTLA-4 binder
Components
  • CTLA-4 binder
  • Cytotoxic T-lymphocyte protein 4
KeywordsDE NOVO PROTEIN/Immune System / CTLA-4 / De novo protein design / high affinity binder / IMMUNE SYSTEM / DE NOVO PROTEIN-Immune System complex
Function / homology
Function and homology information


protein complex involved in cell adhesion / negative regulation of regulatory T cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / clathrin-coated endocytic vesicle / Co-inhibition by CTLA4 / negative regulation of B cell proliferation / negative regulation of T cell proliferation / B cell receptor signaling pathway / T cell receptor signaling pathway / adaptive immune response ...protein complex involved in cell adhesion / negative regulation of regulatory T cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / clathrin-coated endocytic vesicle / Co-inhibition by CTLA4 / negative regulation of B cell proliferation / negative regulation of T cell proliferation / B cell receptor signaling pathway / T cell receptor signaling pathway / adaptive immune response / immune response / positive regulation of apoptotic process / external side of plasma membrane / DNA damage response / perinuclear region of cytoplasm / Golgi apparatus / plasma membrane
Similarity search - Function
Cytotoxic T-lymphocyte antigen 4 / Cytotoxic T-lymphocyte protein 4/CD28 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
: / Cytotoxic T-lymphocyte protein 4
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å
AuthorsYang, W. / Almo, S.C. / Baker, D. / Ghosh, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)S10 OD020068 United States
CitationJournal: Biorxiv / Year: 2024
Title: Design of High Affinity Binders to Convex Protein Target Sites.
Authors: Yang, W. / Hicks, D.R. / Ghosh, A. / Schwartze, T.A. / Conventry, B. / Goreshnik, I. / Allen, A. / Halabiya, S.F. / Kim, C.J. / Hinck, C.S. / Lee, D.S. / Bera, A.K. / Li, Z. / Wang, Y. / ...Authors: Yang, W. / Hicks, D.R. / Ghosh, A. / Schwartze, T.A. / Conventry, B. / Goreshnik, I. / Allen, A. / Halabiya, S.F. / Kim, C.J. / Hinck, C.S. / Lee, D.S. / Bera, A.K. / Li, Z. / Wang, Y. / Schlichthaerle, T. / Cao, L. / Huang, B. / Garrett, S. / Gerben, S.R. / Rettie, S. / Heine, P. / Murray, A. / Edman, N. / Carter, L. / Stewart, L. / Almo, S. / Hinck, A.P. / Baker, D.
History
DepositionFeb 22, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 21, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 16, 2024Group: Structure summary
Category: audit_author / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification
Revision 1.3Oct 23, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.identifier_ORCID / _audit_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CTLA-4 binder
B: Cytotoxic T-lymphocyte protein 4
C: CTLA-4 binder
D: Cytotoxic T-lymphocyte protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6475
Polymers52,6084
Non-polymers391
Water905
1
A: CTLA-4 binder
B: Cytotoxic T-lymphocyte protein 4


Theoretical massNumber of molelcules
Total (without water)26,3042
Polymers26,3042
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1800 Å2
ΔGint-13 kcal/mol
Surface area10730 Å2
MethodPISA
2
C: CTLA-4 binder
D: Cytotoxic T-lymphocyte protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,3433
Polymers26,3042
Non-polymers391
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2250 Å2
ΔGint-13 kcal/mol
Surface area10580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)175.749, 33.604, 74.474
Angle α, β, γ (deg.)90.00, 101.15, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CTLA-4 binder


Mass: 12793.652 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Plasmid: pET29 / Production host: Escherichia coli BL21(DE3) (bacteria)
#2: Protein Cytotoxic T-lymphocyte protein 4 / Cytotoxic T-lymphocyte-associated antigen 4 / CTLA-4


Mass: 13510.340 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTLA4, CD152 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P16410
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.05 Å3/Da / Density % sol: 40.02 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 22% (w/v) PEG 3350 and 0.2 M KCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.72→25 Å / Num. obs: 11876 / % possible obs: 99.8 % / Redundancy: 3.7 % / CC1/2: 0.99 / CC star: 0.99 / Rmerge(I) obs: 0.087 / Net I/σ(I): 10.35
Reflection shellResolution: 2.72→2.82 Å / Rmerge(I) obs: 0.89 / Mean I/σ(I) obs: 2.08 / Num. unique obs: 1237 / CC1/2: 0.87 / CC star: 0.88

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Processing

Software
NameVersionClassification
Aimlessdata scaling
autoPROCdata reduction
PHASER2.8.3phasing
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→24.95 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.292 548 4.62 %
Rwork0.2471 --
obs0.2496 11862 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.72→24.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3458 0 1 5 3464
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063514
X-RAY DIFFRACTIONf_angle_d1.3274764
X-RAY DIFFRACTIONf_dihedral_angle_d13.598476
X-RAY DIFFRACTIONf_chiral_restr0.055564
X-RAY DIFFRACTIONf_plane_restr0.03610
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.72-2.990.3741480.35392751X-RAY DIFFRACTION99
2.99-3.420.35311260.29652805X-RAY DIFFRACTION100
3.42-4.310.33241150.25062846X-RAY DIFFRACTION100
4.31-24.950.25781590.21422912X-RAY DIFFRACTION100
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)
19.91993.4230.72188.5953-2.12038.4669-0.2906-0.4579-0.33012.41640.90970.4517-0.8975-1.015-0.12840.8592-0.00760.09790.6038-0.02680.7528-31.583-8.9065.424
24.77122.98580.32412.7420.69237.2808-1.05940.20380.0696-3.04980.09121.29520.4037-1.32160.28980.73880.01060.01570.7396-0.05720.7488-29.411-6.284-4.816
34.6836-4.4193-3.63738.2101-3.14867.7111-0.6886-0.0965-0.26250.00430.68570.29390.0366-0.0460.12960.7052-0.0606-0.01230.5724-0.05190.6943-22.336-6.7890.835
43.3284-2.84281.58498.8278-1.37895.6719-1.08291.75080.462-2.55970.7657-1.0364-1.64051.33270.20280.77260.01080.13570.64910.09490.7656-16.455-4.112-7.127
58.03450.10340.90266.5674-1.51337.81180.0449-0.0661-0.4021-1.37780.1215-0.9926-0.10680.7273-0.37520.81790.03270.09920.6488-0.04690.8179-11.178-5.261.574
63.232-2.61133.81652.2754-3.78614.6365-0.253-1.01480.71430.25010.255-0.5072-0.91380.84430.42670.654-0.0591-0.03671.4101-0.31330.7121-3.759-8.96321.578
75.6980.70883.26847.1443-2.26439.74730.0254-1.22990.1040.0719-0.02570.35740.8054-0.2659-0.17890.79770.0176-0.00390.6094-0.13510.529-12.311-11.58312.796
84.8416-0.11934.84735.04811.05224.8163-2.60921.1158-0.57921.78651.4661-0.69731.8853-0.80870.52741.3602-0.02530.25551.23030.45081.3748-11.749-21.58816.421
95.6173-1.4835-0.98123.47990.21074.4009-0.3694-1.26550.37430.08830.2227-0.13020.0320.48940.08120.7073-0.04010.01220.59980.01860.5576-8.53-10.99315.998
1010.17240.637-1.58142.30621.66465.7612-0.15230.9655-0.2463-0.23891.1585-1.8415-0.68730.744-0.78870.87350.00450.03030.58610.02820.4449-39.4231.79213.127
118.86210.02551.98243.1459-0.40997.9040.0280.43280.3874-1.36791.25072.2091-0.3104-0.6582-1.00420.63990.11590.01680.89270.04490.6122-49.824-0.74714.229
129.7022.8685-0.73934.2506-0.5884.69760.2661-0.53050.0255-1.6597-0.1146-1.54510.21440.2344-0.39070.53380.0408-0.00730.49470.00740.3713-44.553-0.84921.659
133.54951.97632.44143.07220.02367.0262-0.2364-1.2737-1.22470.35641.41362.5230.256-1.4009-0.64380.5485-0.040.00111.00270.17050.8853-52.468-4.18826.928
148.3425-2.50021.75535.70036.22269.67850.2291-1.42860.93080.68420.7365-0.2287-0.474-1.1289-1.26230.6429-0.1330.10150.67750.13410.5701-44.194-2.69732.894
158.8363-0.29455.34926.35481.11714.38850.2909-0.47540.24471.4130.1417-1.15330.8321.4192-0.68650.8174-0.0228-0.33130.70190.00921.0246-25.757-0.1441.95
166.46315.4777-4.6599.3096-5.83684.87380.15043.71980.4316-5.32370.48552.11411.34380.74111.15781.4322-0.04980.35961.7934-0.08731.2962-24.9112.46322.294
176.4657-2.66582.97433.0417-1.63942.7845-0.4281-0.43681.1152-1.36074.40074.14871.7967-5.4865-0.5480.7371-0.2323-0.14181.0441-0.12920.7759-37.5970.63637.291
184.03423.7124-0.91484.5887-1.50533.2332-0.032-1.36512.1096-1.03920.47751.95760.10130.13060.00840.9840.02410.11740.74750.09010.9077-35.077.18434.339
196.2279-3.54.92044.6543-1.87623.9545-2.0442-0.54571.4885-1.33751.7861-1.58680.65441.8405-0.25271.5677-0.3694-0.08690.9635-0.16541.0615-31.05613.04534.796
203.6039-2.9681-1.71543.91661.90227.8486-1.17771.4561-1.24230.46270.6081-2.75120.62982.0960.46230.8881-0.35920.10761.1215-0.05871.0768-24.4226.78136.075
214.470.32512.72337.89082.53565.92740.5757-1.0584-0.52551.00730.3636-0.13320.5555-0.7125-1.16090.4594-0.0748-0.0060.83020.10160.6945-33.5831.09434.566
226.2929-0.0764-3.83325.55117.35152.0121-0.10471.296-0.57543.1038-1.6931-0.50233.0149-1.31560.0221.48130.0364-0.421.26350.21331.1286-29.564-2.70750.146
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 2:22 )A2 - 22
2X-RAY DIFFRACTION2( CHAIN A AND RESID 23:42 )A23 - 42
3X-RAY DIFFRACTION3( CHAIN A AND RESID 43:65 )A43 - 65
4X-RAY DIFFRACTION4( CHAIN A AND RESID 66:85 )A66 - 85
5X-RAY DIFFRACTION5( CHAIN A AND RESID 86:105 )A86 - 105
6X-RAY DIFFRACTION6( CHAIN B AND RESID 3:24 )B3 - 24
7X-RAY DIFFRACTION7( CHAIN B AND RESID 25:55 )B25 - 55
8X-RAY DIFFRACTION8( CHAIN B AND RESID 56:67 )B56 - 67
9X-RAY DIFFRACTION9( CHAIN B AND RESID 68:117 )B68 - 117
10X-RAY DIFFRACTION10( CHAIN C AND RESID 2:22 )C2 - 22
11X-RAY DIFFRACTION11( CHAIN C AND RESID 23:42 )C23 - 42
12X-RAY DIFFRACTION12( CHAIN C AND RESID 43:65 )C43 - 65
13X-RAY DIFFRACTION13( CHAIN C AND RESID 66:86 )C66 - 86
14X-RAY DIFFRACTION14( CHAIN C AND RESID 87:104 )C87 - 104
15X-RAY DIFFRACTION15( CHAIN D AND RESID 3:24 )D3 - 24
16X-RAY DIFFRACTION16( CHAIN D AND RESID 25:32 )D25 - 32
17X-RAY DIFFRACTION17( CHAIN D AND RESID 33:45 )D33 - 45
18X-RAY DIFFRACTION18( CHAIN D AND RESID 46:55 )D46 - 55
19X-RAY DIFFRACTION19( CHAIN D AND RESID 56:67 )D56 - 67
20X-RAY DIFFRACTION20( CHAIN D AND RESID 68:81 )D68 - 81
21X-RAY DIFFRACTION21( CHAIN D AND RESID 82:111 )D82 - 111
22X-RAY DIFFRACTION22( CHAIN D AND RESID 112:117 )D112 - 117

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