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- PDB-8u6j: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 8u6j
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with N-(2-(5-chloro-2-((2-cyanoindolizin-8-yl)oxy)phenoxy)ethyl)-N-methylacrylamide (JLJ746), 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 / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase / RNA stem-loop binding ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase / RNA stem-loop binding / viral penetration into host nucleus / host multivesicular body / 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 / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont entry into host cell / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / zinc ion binding
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 / Matrix protein, lentiviral and alpha-retroviral, N-terminal / RNase H type-1 domain profile. / Ribonuclease H domain / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retroviral matrix protein / 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. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Chem-VR9 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)114,4514
Polymers114,0292
Non-polymers4222
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint-20 kcal/mol
Surface area44120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.431, 69.630, 105.065
Angle α, β, γ (deg.)90.00, 105.89, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Reverse transcriptase/ribonuclease H / Exoribonuclease H / p66 RT


Mass: 63989.238 Da / Num. of mol.: 1 / Mutation: C879S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Production host: Escherichia coli (E. coli)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H
#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
#3: Chemical ChemComp-VR9 / N-[2-(5-chloro-2-{[(4R)-2-cyanoindolizin-8-yl]oxy}phenoxy)ethyl]-N-methylpropanamide


Mass: 397.855 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 3.46 Å3/Da / Density % sol: 64.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 50 mM HEPES pH 7.0, 17.5% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 7.0-7.8

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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: Nov 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.64→107.926 Å / Num. obs: 45364 / % possible obs: 98.2 % / Redundancy: 4.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.068 / Rrim(I) all: 0.107 / Net I/σ(I): 7.6
Reflection shellResolution: 2.64→2.686 Å / Rmerge(I) obs: 1.384 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2319 / CC1/2: 0.326 / Rpim(I) all: 1.171 / Rrim(I) all: 1.823

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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: 2.64→43.26 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 37.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2739 1997 4.47 %
Rwork0.239 --
obs0.2406 44698 96.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.64→43.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7286 0 29 11 7326
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0097550
X-RAY DIFFRACTIONf_angle_d0.98510353
X-RAY DIFFRACTIONf_dihedral_angle_d16.9872638
X-RAY DIFFRACTIONf_chiral_restr0.0551157
X-RAY DIFFRACTIONf_plane_restr0.0081322
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.64-2.710.45191270.46722715X-RAY DIFFRACTION87
2.71-2.780.4411390.42782977X-RAY DIFFRACTION95
2.78-2.860.39471460.38053100X-RAY DIFFRACTION99
2.86-2.950.4111450.34223121X-RAY DIFFRACTION99
2.95-3.060.38541460.33323103X-RAY DIFFRACTION99
3.06-3.180.37991450.31773112X-RAY DIFFRACTION100
3.18-3.330.3711470.30353140X-RAY DIFFRACTION100
3.33-3.50.35741460.28693137X-RAY DIFFRACTION100
3.5-3.720.38661430.3193063X-RAY DIFFRACTION98
3.72-4.010.27791210.25632568X-RAY DIFFRACTION81
4.01-4.410.22521470.20383141X-RAY DIFFRACTION99
4.41-5.050.20011460.19393146X-RAY DIFFRACTION99
5.05-6.360.2711480.21843155X-RAY DIFFRACTION99
6.36-43.260.21131510.17883223X-RAY DIFFRACTION98

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