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- PDB-8u6s: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 8u6s
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 8-(2-(3-morpholino-3-oxopropoxy)phenoxy)indolizine-2-carbonitrile (JLJ757), 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
PHOSPHATE ION / Chem-VPB / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 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)114,4196
Polymers113,8142
Non-polymers6064
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5170 Å2
ΔGint-42 kcal/mol
Surface area44130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)222.126, 68.624, 103.701
Angle α, β, γ (deg.)90.00, 107.41, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Reverse transcriptase/ribonuclease H


Mass: 63774.023 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, 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

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Non-polymers , 4 types, 16 molecules

#3: Chemical ChemComp-VPB / (4S)-8-{2-[3-(morpholin-4-yl)-3-oxopropoxy]phenoxy}indolizine-2-carbonitrile


Mass: 391.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.31 Å3/Da / Density % sol: 62.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 50 mM Imidazole pH 6.8, 15% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.8-7.8

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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: Jun 28, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.99→105.975 Å / Num. obs: 30403 / % possible obs: 99.8 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.052 / Rrim(I) all: 0.1 / Net I/σ(I): 12.8
Reflection shellResolution: 2.99→3.04 Å / Redundancy: 7.3 % / Rmerge(I) obs: 2.366 / Num. unique obs: 1510 / CC1/2: 0.369 / Rpim(I) all: 1.42 / Rrim(I) all: 2.765 / % 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: 2.99→51.07 Å / SU ML: 0.58 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 36.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2993 1516 5 %
Rwork0.2248 --
obs0.2285 30323 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.99→51.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7413 0 11 13 7437
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.017719
X-RAY DIFFRACTIONf_angle_d1.09610553
X-RAY DIFFRACTIONf_dihedral_angle_d18.1592771
X-RAY DIFFRACTIONf_chiral_restr0.0571177
X-RAY DIFFRACTIONf_plane_restr0.0081332
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.99-3.090.42941340.37622554X-RAY DIFFRACTION98
3.09-3.20.38851360.33632578X-RAY DIFFRACTION100
3.2-3.330.3581370.31422596X-RAY DIFFRACTION100
3.33-3.480.40131380.312625X-RAY DIFFRACTION100
3.48-3.660.3691380.2722619X-RAY DIFFRACTION100
3.66-3.890.32661370.25212609X-RAY DIFFRACTION100
3.89-4.190.32741380.24472605X-RAY DIFFRACTION100
4.19-4.610.29311380.21312620X-RAY DIFFRACTION100
4.61-5.280.30161380.20842640X-RAY DIFFRACTION100
5.28-6.650.30351400.2342649X-RAY DIFFRACTION100
6.65-51.070.231420.16952712X-RAY DIFFRACTION99

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