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- PDB-8u6i: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 8u6i
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with N-(2-(2-((2-cyanoindolizin-8-yl)oxy)phenoxy)ethyl)-N-methylacrylamide (JLJ745), 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
Chem-VVN / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 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)114,4086
Polymers113,9722
Non-polymers4364
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5360 Å2
ΔGint-50 kcal/mol
Surface area44770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)221.730, 67.932, 103.333
Angle α, β, γ (deg.)90.00, 107.81, 90.00
Int Tables number5
Space group name H-MC121

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Components

#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
#3: Chemical ChemComp-VVN / N-[2-(2-{[(4R)-2-cyanoindolizin-8-yl]oxy}phenoxy)ethyl]-N-methylpropanamide


Mass: 363.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 3.25 Å3/Da / Density % sol: 62.14 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.3
Details: 50 mM Imidazole pH 6.3, 17.5% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.3-7.8

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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: 2.459→98.383 Å / Num. obs: 53557 / % possible obs: 99.9 % / Redundancy: 6.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.073 / Rrim(I) all: 0.138 / Net I/σ(I): 9.5
Reflection shellResolution: 2.459→2.502 Å / Rmerge(I) obs: 2.259 / Mean I/σ(I) obs: 1 / Num. unique obs: 2652 / CC1/2: 0.375 / Rpim(I) all: 1.382 / Rrim(I) all: 2.652 / % possible all: 100

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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: 2.46→32.7 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2776 2000 3.75 %
Rwork0.2205 --
obs0.2227 53400 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.46→32.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7745 0 3 20 7768
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087985
X-RAY DIFFRACTIONf_angle_d0.99310867
X-RAY DIFFRACTIONf_dihedral_angle_d16.2832974
X-RAY DIFFRACTIONf_chiral_restr0.0521185
X-RAY DIFFRACTIONf_plane_restr0.0071366
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.46-2.520.42211400.35993603X-RAY DIFFRACTION98
2.52-2.590.34571400.33163578X-RAY DIFFRACTION99
2.59-2.660.38651410.3133649X-RAY DIFFRACTION100
2.66-2.750.3581430.30333676X-RAY DIFFRACTION100
2.75-2.850.37371420.30663647X-RAY DIFFRACTION100
2.85-2.960.36361420.29513649X-RAY DIFFRACTION100
2.96-3.10.30771420.27533669X-RAY DIFFRACTION100
3.1-3.260.32961440.25263678X-RAY DIFFRACTION100
3.26-3.470.36251420.26013654X-RAY DIFFRACTION100
3.47-3.730.27561430.23023697X-RAY DIFFRACTION100
3.73-4.110.2371440.20133685X-RAY DIFFRACTION100
4.11-4.70.26971430.18053690X-RAY DIFFRACTION100
4.7-5.920.26581450.19053722X-RAY DIFFRACTION100
5.92-32.70.20451490.17663803X-RAY DIFFRACTION100

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