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- PDB-8eaa: NKG2D complexed with inhibitor 4e -

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Basic information

Entry
Database: PDB / ID: 8eaa
TitleNKG2D complexed with inhibitor 4e
ComponentsNKG2-D type II integral membrane protein
KeywordsIMMUNOSUPPRESSANT/INHIBITOR / NKG2D / Immune System / IMMUNOSUPPRESSANT / IMMUNOSUPPRESSANT-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of natural killer cell chemotaxis / MHC class Ib receptor activity / positive regulation of natural killer cell mediated cytotoxicity / natural killer cell activation / negative regulation of GTPase activity / natural killer cell mediated cytotoxicity / stimulatory C-type lectin receptor signaling pathway / MHC class I protein binding / nitric oxide biosynthetic process / T cell costimulation ...negative regulation of natural killer cell chemotaxis / MHC class Ib receptor activity / positive regulation of natural killer cell mediated cytotoxicity / natural killer cell activation / negative regulation of GTPase activity / natural killer cell mediated cytotoxicity / stimulatory C-type lectin receptor signaling pathway / MHC class I protein binding / nitric oxide biosynthetic process / T cell costimulation / DAP12 interactions / positive regulation of type II interferon production / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / positive regulation of nitric oxide biosynthetic process / DAP12 signaling / signaling receptor activity / cellular response to lipopolysaccharide / carbohydrate binding / adaptive immune response / cell differentiation / defense response to Gram-positive bacterium / external side of plasma membrane / cell surface / signal transduction / identical protein binding / membrane / plasma membrane
Similarity search - Function
NKG2-D type II integral membrane protein / Natural killer cell receptor-like, C-type lectin-like domain / Lectin C-type domain / C-type lectin domain profile. / C-type lectin-like / C-type lectin (CTL) or carbohydrate-recognition domain (CRD) / C-type lectin-like/link domain superfamily / C-type lectin fold
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Chem-VMW / NKG2-D type II integral membrane protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.57 Å
AuthorsThompson, A.A. / Grant, J.C. / Karpowich, N.K. / Sharma, S.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: Identification of small-molecule protein-protein interaction inhibitors for NKG2D.
Authors: Thompson, A.A. / Harbut, M.B. / Kung, P.P. / Karpowich, N.K. / Branson, J.D. / Grant, J.C. / Hagan, D. / Pascual, H.A. / Bai, G. / Zavareh, R.B. / Coate, H.R. / Collins, B.C. / Cote, M. / ...Authors: Thompson, A.A. / Harbut, M.B. / Kung, P.P. / Karpowich, N.K. / Branson, J.D. / Grant, J.C. / Hagan, D. / Pascual, H.A. / Bai, G. / Zavareh, R.B. / Coate, H.R. / Collins, B.C. / Cote, M. / Gelin, C.F. / Damm-Ganamet, K.L. / Gholami, H. / Huff, A.R. / Limon, L. / Lumb, K.J. / Mak, P.A. / Nakafuku, K.M. / Price, E.V. / Shih, A.Y. / Tootoonchi, M. / Vellore, N.A. / Wang, J. / Wei, N. / Ziff, J. / Berger, S.B. / Edwards, J.P. / Gardet, A. / Sun, S. / Towne, J.E. / Venable, J.D. / Shi, Z. / Venkatesan, H. / Rives, M.L. / Sharma, S. / Shireman, B.T. / Allen, S.J.
History
DepositionAug 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 10, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 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
B: NKG2-D type II integral membrane protein
A: NKG2-D type II integral membrane protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,5756
Polymers29,7622
Non-polymers8144
Water3,783210
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-2 kcal/mol
Surface area11210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.013, 43.338, 67.109
Angle α, β, γ (deg.)90.00, 106.49, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-505-

HOH

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Components

#1: Protein NKG2-D type II integral membrane protein / Killer cell lectin-like receptor subfamily K member 1 / NK cell receptor D / NKG2-D-activating NK receptor


Mass: 14880.832 Da / Num. of mol.: 2 / Mutation: S117E,I173S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KLRK1, D12S2489E, NKG2D / Production host: Escherichia coli (E. coli) / References: UniProt: P26718
#2: Chemical ChemComp-VMW / N-{(1S)-2-(dimethylamino)-1-[3-methyl-5-(trifluoromethyl)phenyl]-2-oxoethyl}-4-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide


Mass: 509.444 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C25H21F6N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 2.34 Å3/Da / Density % sol: 47.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.15 - 0.22 M NaNO3 20 - 31 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Jun 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.57→64.35 Å / Num. obs: 37722 / % possible obs: 97.3 % / Redundancy: 3.1 % / Biso Wilson estimate: 13.481 Å2 / Rpim(I) all: 0.034 / Rrim(I) all: 0.063 / Net I/σ(I): 13.1 / Num. measured all: 117470
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
1.57-1.61.94.2287014910.110.1776.3
4.26-64.43.421.3683920300.0310.05899.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660: ???)refinement
xia2data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MPU

1mpu


Resolution: 1.57→32.03 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 19.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2038 1947 5.16 %
Rwork0.1719 --
obs0.1735 37714 97.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.57→32.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1963 0 56 210 2229
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062094
X-RAY DIFFRACTIONf_angle_d0.8992838
X-RAY DIFFRACTIONf_dihedral_angle_d6.363278
X-RAY DIFFRACTIONf_chiral_restr0.089283
X-RAY DIFFRACTIONf_plane_restr0.005364
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.57-1.610.20681040.18472069X-RAY DIFFRACTION78
1.61-1.650.2411200.17532276X-RAY DIFFRACTION88
1.65-1.70.18421390.16242554X-RAY DIFFRACTION97
1.7-1.760.22081510.1742577X-RAY DIFFRACTION100
1.76-1.820.1951410.17132642X-RAY DIFFRACTION100
1.82-1.890.20651450.1752565X-RAY DIFFRACTION100
1.89-1.980.20561590.1722586X-RAY DIFFRACTION100
1.98-2.080.19231370.17162622X-RAY DIFFRACTION100
2.08-2.210.20341230.16432629X-RAY DIFFRACTION100
2.21-2.380.18241520.17692628X-RAY DIFFRACTION100
2.38-2.620.18421370.17372618X-RAY DIFFRACTION100
2.62-30.22521450.1862634X-RAY DIFFRACTION100
3-3.780.22431450.17542640X-RAY DIFFRACTION100
3.78-32.030.1941490.16142727X-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)
10.7690.19920.88581.8004-0.73151.5439-0.01170.08820.1978-0.0206-0.0539-0.0291-0.19960.16660.01260.14410.00510.00960.1359-0.00190.10560.5918-11.329910.2647
22.30040.2095-0.46692.1714-0.54321.6423-0.0326-0.0511-0.1041-0.0680.02860.0286-0.0183-0.08740.00730.1068-0.0019-0.00510.1158-0.01510.0885-4.3218-22.906616.1125
32.5755-0.2021.00382.8860.29613.4157-0.13060.7438-0.7105-0.48320.00550.39730.4599-0.2991-0.02990.2817-0.0573-0.03520.2344-0.0910.2577-6.6237-33.64928.5345
41.6238-0.3206-0.3232.28910.39121.0765-0.01550.0315-0.1799-0.08690.0116-0.06470.073-0.0055-0.00850.1166-0.0028-0.00290.1341-0.01150.138-3.3395-29.653718.0948
53.6298-0.03591.8373.0925-0.21152.7632-0.04590.1842-0.1018-0.49080.15270.1342-0.21810.1366-0.08190.1933-0.019-0.01270.1743-0.01490.14484.8228-7.29626.6866
63.5993-0.89681.36262.76990.08571.96180.00310.1561-0.0533-0.0475-0.04870.0287-0.0505-0.00210.06430.1538-0.00310.00340.1492-0.00350.10958.876-8.596614.0303
72.90680.89261.82611.07230.73993.12030.02850.6285-0.4526-0.14380.1157-0.16940.05680.1855-0.04930.1264-0.010.0280.2321-0.05640.194924.508-11.07516.2729
82.6630.08690.52131.39680.44421.3692-0.07120.066-0.1067-0.0479-0.0240.0456-0.0864-0.06270.05330.1282-0.00650.00490.1049-0.00490.115211.2024-7.005122.2226
93.35220.60070.99452.01281.95033.1519-0.2243-0.27370.98710.60170.0948-0.4237-0.82460.386-0.01390.3379-0.0566-0.08320.2044-0.03350.267322.45051.806527.8702
102.5010.5992-0.06361.29780.7161.7238-0.1254-0.2440.11860.0092-0.0267-0.2089-0.27750.16610.05870.188-0.0149-0.04490.1446-0.02690.208118.069-1.789130.4801
112.72180.21420.12230.96090.66371.7031-0.0454-0.0408-0.1191-0.06250.0315-0.0763-0.14430.08770.06640.1111-0.0052-0.00350.09920.00170.135417.8798-8.938524.2957
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 91 through 114 )
2X-RAY DIFFRACTION2chain 'B' and (resid 115 through 156 )
3X-RAY DIFFRACTION3chain 'B' and (resid 157 through 179 )
4X-RAY DIFFRACTION4chain 'B' and (resid 180 through 216 )
5X-RAY DIFFRACTION5chain 'A' and (resid 93 through 103 )
6X-RAY DIFFRACTION6chain 'A' and (resid 104 through 114 )
7X-RAY DIFFRACTION7chain 'A' and (resid 115 through 130 )
8X-RAY DIFFRACTION8chain 'A' and (resid 131 through 156 )
9X-RAY DIFFRACTION9chain 'A' and (resid 157 through 168 )
10X-RAY DIFFRACTION10chain 'A' and (resid 169 through 188 )
11X-RAY DIFFRACTION11chain 'A' and (resid 189 through 215 )

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