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- PDB-8u6t: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 8u6t
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 5-(2-(2-(3-acryloyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)phenoxy)-2-naphthonitrile (JLJ758), a non-nucleoside inhibitor
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsVIRAL PROTEIN / REVERSE TRANSCRIPTASE / ANTIVIRAL / DRUG DESIGN / HIV-1
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / symbiont-mediated suppression of host gene expression / viral penetration into host nucleus / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / host cell / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / Hydrolases; Acting on ester bonds / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / viral translational frameshifting / lipid binding / host cell nucleus / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / DNA binding / zinc ion binding / membrane
Similarity search - Function
Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retropepsin-like catalytic domain / RNase H type-1 domain profile. / Ribonuclease H domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retroviral matrix protein / Retrovirus capsid, C-terminal / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Ribonuclease H superfamily / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
PHOSPHATE ION / Chem-VO8 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsPrucha, G. / Henry, S. / Jorgensen, W.L. / Anderson, K.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIH/NAD AI155072 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase.
Authors: Prucha, G.R. / Henry, S. / Hollander, K. / Carter, Z.J. / Spasov, K.A. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionSep 13, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,7838
Polymers113,9722
Non-polymers8116
Water63135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5710 Å2
ΔGint-48 kcal/mol
Surface area43900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)222.153, 67.265, 103.259
Angle α, β, γ (deg.)90.00, 108.10, 90.00
Int Tables number5
Space group name H-MC121
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Reverse transcriptase/ribonuclease H


Mass: 63932.180 Da / Num. of mol.: 1 / Mutation: C879S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag-pol / Production host: Escherichia coli (E. coli) / References: UniProt: P03366
#2: Protein p51 RT


Mass: 50039.488 Da / Num. of mol.: 1 / Mutation: C879S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag-pol / Production host: Escherichia coli (E. coli) / References: UniProt: P03366

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Non-polymers , 4 types, 41 molecules

#3: Chemical ChemComp-VO8 / 5-(2-{2-[2-oxo-3-(prop-2-enoyl)-2,3-dihydro-1H-benzimidazol-1-yl]ethoxy}phenoxy)naphthalene-2-carbonitrile


Mass: 477.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H23N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 35 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.22 Å3/Da / Density % sol: 61.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50 mM MES pH 5.5, 17.5% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 5.5-7.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 14, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.248→98.148 Å / Num. obs: 69127 / % possible obs: 99.8 % / Redundancy: 4.7 % / Biso Wilson estimate: 58.46 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.062 / Rrim(I) all: 0.099 / Net I/σ(I): 6.1
Reflection shellResolution: 2.248→2.287 Å / Redundancy: 4.8 % / Rmerge(I) obs: 1.986 / Num. unique obs: 3386 / CC1/2: 0.34 / Rpim(I) all: 1.589 / Rrim(I) all: 2.552 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→36.98 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 35.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2867 1998 2.92 %
Rwork0.2466 --
obs0.2477 68442 98.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.25→36.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7647 0 17 36 7700
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087914
X-RAY DIFFRACTIONf_angle_d0.97210765
X-RAY DIFFRACTIONf_dihedral_angle_d14.3172966
X-RAY DIFFRACTIONf_chiral_restr0.0531179
X-RAY DIFFRACTIONf_plane_restr0.011357
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.30.41941280.41254251X-RAY DIFFRACTION90
2.3-2.370.41681400.38784643X-RAY DIFFRACTION97
2.37-2.440.37981400.35864695X-RAY DIFFRACTION99
2.44-2.510.35281440.33424795X-RAY DIFFRACTION100
2.51-2.60.34491440.32134793X-RAY DIFFRACTION100
2.6-2.710.34261440.29194765X-RAY DIFFRACTION100
2.71-2.830.30181440.27564797X-RAY DIFFRACTION100
2.83-2.980.35131420.28264741X-RAY DIFFRACTION100
2.98-3.170.35781440.29614791X-RAY DIFFRACTION100
3.17-3.410.30311450.28384818X-RAY DIFFRACTION100
3.41-3.760.28571440.25024804X-RAY DIFFRACTION100
3.76-4.30.26041440.22554794X-RAY DIFFRACTION100
4.3-5.410.24911460.20264805X-RAY DIFFRACTION99
5.41-36.980.2461490.20144952X-RAY DIFFRACTION100

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