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- PDB-7m41: Structure of TIM-3 in complex with N-(4-(8-chloro-2-methyl-5-oxo-... -

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Basic information

Entry
Database: PDB / ID: 7m41
TitleStructure of TIM-3 in complex with N-(4-(8-chloro-2-methyl-5-oxo-5,6-dihydro-[1,2,4]traizolo[1,5-c]quinazolin-9-yl)-3-methylphenyl)-1H-imidazole-2-sulfonamide (compound 38)
ComponentsHepatitis A virus cellular receptor 2
KeywordsIMMUNE SYSTEM / IgV
Function / homology
Function and homology information


regulation of tolerance induction dependent upon immune response / negative regulation of interleukin-3 production / negative regulation of granulocyte colony-stimulating factor production / negative regulation of myeloid dendritic cell activation / Interleukin-2 family signaling / negative regulation of interferon-alpha production / negative regulation of T-helper 1 type immune response / negative regulation of defense response to bacterium / natural killer cell tolerance induction / toll-like receptor 7 signaling pathway ...regulation of tolerance induction dependent upon immune response / negative regulation of interleukin-3 production / negative regulation of granulocyte colony-stimulating factor production / negative regulation of myeloid dendritic cell activation / Interleukin-2 family signaling / negative regulation of interferon-alpha production / negative regulation of T-helper 1 type immune response / negative regulation of defense response to bacterium / natural killer cell tolerance induction / toll-like receptor 7 signaling pathway / negative regulation of natural killer cell activation / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / positive regulation of defense response to bacterium / negative regulation of immunological synapse formation / toll-like receptor 3 signaling pathway / negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell / positive regulation of interleukin-1 production / toll-like receptor 9 signaling pathway / mediator complex / macrophage activation involved in immune response / positive regulation of macrophage activation / anchoring junction / negative regulation of interleukin-2 production / : / positive regulation of interleukin-4 production / negative regulation of type II interferon production / negative regulation of interleukin-6 production / immunological synapse / negative regulation of tumor necrosis factor production / maternal process involved in female pregnancy / positive regulation of chemokine production / negative regulation of T cell proliferation / positive regulation of T cell proliferation / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / transmembrane signaling receptor activity / cellular response to lipopolysaccharide / adaptive immune response / early endosome / positive regulation of ERK1 and ERK2 cascade / defense response to Gram-positive bacterium / inflammatory response / negative regulation of gene expression / innate immune response / regulation of transcription by RNA polymerase II / cell surface / metal ion binding / plasma membrane
Similarity search - Function
: / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Chem-YQG / Hepatitis A virus cellular receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.79 Å
AuthorsRietz, T.A.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3).
Authors: Rietz, T.A. / Teuscher, K.B. / Mills, J.J. / Gogliotti, R.D. / Lepovitz, L.T. / Scaggs, W.R. / Yoshida, K. / Luong, K. / Lee, T. / Fesik, S.W.
History
DepositionMar 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 30, 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: Hepatitis A virus cellular receptor 2
B: Hepatitis A virus cellular receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6166
Polymers24,5962
Non-polymers1,0204
Water4,216234
1
A: Hepatitis A virus cellular receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,8083
Polymers12,2981
Non-polymers5102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Hepatitis A virus cellular receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,8083
Polymers12,2981
Non-polymers5102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.215, 46.828, 53.905
Angle α, β, γ (deg.)90.000, 93.050, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Hepatitis A virus cellular receptor 2 / HAVcr-2 / T-cell immunoglobulin and mucin domain-containing protein 3 / TIMD-3 / T-cell ...HAVcr-2 / T-cell immunoglobulin and mucin domain-containing protein 3 / TIMD-3 / T-cell immunoglobulin mucin receptor 3 / TIM-3 / T-cell membrane protein 3


Mass: 12298.002 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HAVCR2, TIM3, TIMD3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8TDQ0
#2: Chemical ChemComp-YQG / N-{4-[(4S,10aP)-8-chloro-2-methyl-5-oxo-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-9-yl]-3-methylphenyl}-1H-imidazole-2-sulfonamide


Mass: 469.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16ClN7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.18 Å3/Da / Density % sol: 43.66 % / Mosaicity: 0.827 °
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.8 M sodium tartrate dibasic dihydrate, 0.1 M HEPES pH 6.8-8.2, and 10 mM CaCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.987 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Nov 26, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.79→30 Å / Num. obs: 19569 / % possible obs: 97.8 % / Redundancy: 7.6 % / Biso Wilson estimate: 11.73 Å2 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.034 / Rrim(I) all: 0.095 / Χ2: 2.031 / Net I/σ(I): 11.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.79-1.837.80.2899330.9790.1110.3091.30996.5
1.83-1.867.70.2679910.9820.1030.2861.39596.8
1.86-1.97.80.2369230.9830.0910.2531.43996.6
1.9-1.947.70.2159780.9870.0830.231.55996.8
1.94-1.987.70.1929490.9860.0740.2061.62796.9
1.98-2.037.70.1719900.9880.0660.1831.71397.3
2.03-2.087.70.1689490.9880.0650.181.76597.2
2.08-2.137.70.1479790.990.0570.1581.94797.2
2.13-2.27.70.149630.9930.0540.151.91497.5
2.2-2.277.70.1319740.9920.050.142.05497.8
2.27-2.357.70.1199770.9940.0460.1282.11997.7
2.35-2.447.70.1169850.9930.0450.1252.08298
2.44-2.557.60.1069810.9940.0410.1142.19498.4
2.55-2.697.60.0979730.9950.0380.1042.30398.2
2.69-2.867.60.08610130.9960.0330.0922.29598.4
2.86-3.087.60.0749690.9970.0290.082.34998.5
3.08-3.397.50.0649910.9960.0250.0692.65598.8
3.39-3.887.50.0599980.9980.0230.0632.68799
3.88-4.887.40.0510170.9980.020.0542.50799.4
4.88-307.10.05310360.9980.0210.0572.71599

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.52 Å26.91 Å
Translation3.52 Å26.91 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.8.3phasing
PHENIX1.19.1_4122refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F71

5f71


Resolution: 1.79→26.91 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2127 930 4.75 %
Rwork0.1698 18634 -
obs0.172 19564 97.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.79 Å2 / Biso mean: 15.777 Å2 / Biso min: 3.19 Å2
Refinement stepCycle: final / Resolution: 1.79→26.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1718 0 66 234 2018
Biso mean--13.45 24.17 -
Num. residues----218
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.79-1.890.21451310.17642572270395
1.89-2.010.23241340.16092622275697
2.01-2.160.22241500.17172623277397
2.16-2.380.23451020.18422677277998
2.38-2.720.26821240.19192695281998
2.72-3.430.23781190.16842707282699
3.43-26.910.16581700.15442738290899

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