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- PDB-7u8y: TREX1 Structural Studies Capture Small Molecule Inhibition and Im... -

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Basic information

Entry
Database: PDB / ID: 7u8y
TitleTREX1 Structural Studies Capture Small Molecule Inhibition and Implicate Novel DNA Dynamics
ComponentsThree-prime repair exonuclease 1
KeywordsHYDROLASE/INHIBITOR / Inhibitor / Exonuclease / Immunotherapy / Complex / DNA BINDING PROTEIN / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


immune response in brain or nervous system / adenyl deoxyribonucleotide binding / CD86 biosynthetic process / immune complex formation / cellular response to type I interferon / organ or tissue specific immune response / atrial cardiac muscle tissue development / activation of immune response / DNA synthesis involved in UV-damage excision repair / T cell antigen processing and presentation ...immune response in brain or nervous system / adenyl deoxyribonucleotide binding / CD86 biosynthetic process / immune complex formation / cellular response to type I interferon / organ or tissue specific immune response / atrial cardiac muscle tissue development / activation of immune response / DNA synthesis involved in UV-damage excision repair / T cell antigen processing and presentation / MutSalpha complex binding / retrotransposition / oligosaccharyltransferase complex / regulation of lysosome organization / regulation of fatty acid metabolic process / regulation of lipid biosynthetic process / DNA modification / MutLalpha complex binding / WW domain binding / heart process / regulation of type I interferon production / regulation of protein complex stability / cellular response to hydroxyurea / lymphoid progenitor cell differentiation / exodeoxyribonuclease III / double-stranded DNA 3'-5' DNA exonuclease activity / 3'-5'-DNA exonuclease activity / macrophage activation involved in immune response / regulation of tumor necrosis factor production / regulation of cellular respiration / inflammatory response to antigenic stimulus / regulation of immunoglobulin production / DNA catabolic process / apoptotic cell clearance / regulation of T cell activation / DNA binding, bending / DNA duplex unwinding / regulation of glycolytic process / DNA metabolic process / negative regulation of type I interferon-mediated signaling pathway / cellular response to organic substance / regulation of innate immune response / negative regulation of cGAS/STING signaling pathway / type I interferon-mediated signaling pathway / blood vessel development / nuclear replication fork / cellular response to interferon-beta / heart morphogenesis / response to UV / 3'-5' exonuclease activity / mitotic G1 DNA damage checkpoint signaling / negative regulation of innate immune response / DNA damage checkpoint signaling / kidney development / generation of precursor metabolites and energy / determination of adult lifespan / protein-DNA complex / cellular response to gamma radiation / establishment of protein localization / cellular response to reactive oxygen species / cellular response to UV / single-stranded DNA binding / cellular response to oxidative stress / regulation of inflammatory response / double-stranded DNA binding / regulation of gene expression / defense response to virus / DNA replication / adaptive immune response / protein stabilization / immune response / inflammatory response / innate immune response / DNA damage response / endoplasmic reticulum membrane / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / DNA binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Three-prime repair exonuclease 1/2 / Exonuclease, RNase T/DNA polymerase III / EXOIII / Ribonuclease H superfamily / Ribonuclease H-like superfamily
Similarity search - Domain/homology
ALIZARIN RED / : / Three-prime repair exonuclease 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsHemphill, W.O. / Harvey, S.E. / Simpson, S.R. / Smalley, T.L. / Salsbury, F.R. / Perrino, F.W. / Hollis, T.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI116725 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM110734 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA012197 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)T32-AI007401 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32-GM095440 United States
CitationJournal: to be published
Title: TREX1 Structural Studies Capture Small Molecule Inhibition and Implicate Novel DNA Dynamics
Authors: Hemphill, W.O. / Harvey, S.E. / Simpson, S.R. / Smalley, T.L. / Salsbury, F.R. / Perrino, F.W. / Hollis, T.
History
DepositionMar 9, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Three-prime repair exonuclease 1
B: Three-prime repair exonuclease 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,67810
Polymers50,1772
Non-polymers1,5018
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, TREX1 from gel filtration consistent with size of dimer. Also, there are many additional X-ray structures of TREX enzymes, all with the same dimer configuration.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-24 kcal/mol
Surface area17960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.555, 127.555, 80.010
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Three-prime repair exonuclease 1 / 3'-5' exonuclease TREX1


Mass: 25088.637 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trex1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q91XB0, exodeoxyribonuclease III
#2: Chemical
ChemComp-AZN / ALIZARIN RED / Alizarin


Mass: 320.274 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H8O7S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mn
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 124 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.38 Å3/Da / Density % sol: 48.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: Protein was dialyzed into 20 mM MES (pH 6.5) with 50 mM NaCl. Complex was formed by incubating the protein at 5 mg/mL with 2 mM dAMP and 5 mM MnCl2. 0.3 uL protein complex at 5 mg/ml TREX1 ...Details: Protein was dialyzed into 20 mM MES (pH 6.5) with 50 mM NaCl. Complex was formed by incubating the protein at 5 mg/mL with 2 mM dAMP and 5 mM MnCl2. 0.3 uL protein complex at 5 mg/ml TREX1 was mixed with an equal volume of reservoir solution and placed on a bridge above 50 uL of the reservoir solution. mTREX1-dAMP crystals grew in initial conditions of 0.2 M MES monohydrate, sodium hydroxide (pH 6.2), and 20% w/v polyethylene glycol 4,000. All crystals grew within one week. After crystal formation, 4 mM TIM009 was soaked into mTREX1-dAMP crystals for 5 days. Prior to data collection crystals were dipped into reservoir solution containing 15% glycerol in preparation for cryo-cooling

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Feb 17, 2020 / Details: varimax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.22→50 Å / Num. obs: 23262 / % possible obs: 99.1 % / Redundancy: 9.4 % / Biso Wilson estimate: 37.4 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.025 / Rrim(I) all: 0.077 / Χ2: 1.1 / Net I/σ(I): 30.8
Reflection shellResolution: 2.22→2.29 Å / Rmerge(I) obs: 0.328 / Mean I/σ(I) obs: 5.8 / Num. unique obs: 1804 / CC1/2: 0.953 / CC star: 0.988 / Rpim(I) all: 0.133 / Rrim(I) all: 0.355 / Χ2: 1.027 / % possible all: 89.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PHASERv2.1.2phasing
Cootv0.8.9.2model building
CrysalisProdata collection
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OA8

2oa8


Resolution: 2.22→45.5 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.945 / SU B: 10.347 / SU ML: 0.14 / Cross valid method: THROUGHOUT / ESU R: 0.29 / ESU R Free: 0.206 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.22175 1194 5.1 %RANDOM
Rwork0.18097 ---
obs0.18309 22068 97.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.1 Å / Solvent model: MASK
Displacement parametersBiso mean: 49.402 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å2-0.04 Å20 Å2
2---0.08 Å20 Å2
3---0.26 Å2
Refinement stepCycle: LAST / Resolution: 2.22→45.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3448 0 92 124 3664
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0173629
X-RAY DIFFRACTIONr_bond_other_d0.0010.0193390
X-RAY DIFFRACTIONr_angle_refined_deg1.3431.9134968
X-RAY DIFFRACTIONr_angle_other_deg1.0742.6377826
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2975441
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.66721.149174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.49315577
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1181528
X-RAY DIFFRACTIONr_chiral_restr0.0850.2549
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024027
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02789
X-RAY DIFFRACTIONr_mcbond_it2.0772.5931776
X-RAY DIFFRACTIONr_mcbond_other2.0442.591774
X-RAY DIFFRACTIONr_mcangle_it2.9543.8762213
X-RAY DIFFRACTIONr_mcangle_other2.9263.8752213
X-RAY DIFFRACTIONr_scbond_it3.0663.141853
X-RAY DIFFRACTIONr_scbond_other3.0653.1411854
X-RAY DIFFRACTIONr_scangle_other4.564.6222751
X-RAY DIFFRACTIONr_long_range_B_refined9.52134.9254407
X-RAY DIFFRACTIONr_long_range_B_other9.52934.8194389
LS refinement shellResolution: 2.222→2.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.266 66 -
Rwork0.208 1616 -
obs--93.86 %
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)
13.26410.29970.31642.23360.36043.2654-0.15150.55980.1578-0.32150.00420.048-0.4229-0.38910.14730.1180.0196-0.05650.17260.01020.0563-27.02-8.123-6.008
22.5791-0.13091.20132.31740.26233.15070.1045-0.3995-0.23370.3137-0.02380.03620.3381-0.3599-0.08070.1101-0.0459-0.03050.08010.03570.0431-19.558-20.05816.608
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 234
2X-RAY DIFFRACTION2B6 - 234

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