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- PDB-8str: Crystal Structure of HIV-1 Reverse Transcriptase (Y181C) varient ... -

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Basic information

Entry
Database: PDB / ID: 8str
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C) varient in Complex with 5-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)-4-fluorophenoxy)-7-fluoro-2-naphthonitrile (JLJ636), 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 / 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 / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / lipid binding / symbiont entry into host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / 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 / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / RNase H type-1 domain profile. / Ribonuclease H domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retrovirus capsid, C-terminal / 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-7N1 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.77 Å
AuthorsHollander, K. / Chan, A.H. / 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: Protein Sci. / Year: 2023
Title: Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.
Authors: Hollander, K. / Chan, A.H. / Frey, K.M. / Hunker, O. / Ippolito, J.A. / Spasov, K.A. / Yeh, Y.J. / Jorgensen, W.L. / Ho, Y.C. / Anderson, K.S.
History
DepositionMay 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.identifier_ORCID

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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)114,4043
Polymers113,9692
Non-polymers4351
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5130 Å2
ΔGint-30 kcal/mol
Surface area45610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.730, 74.040, 107.830
Angle α, β, γ (deg.)90.00, 99.09, 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: 63929.207 Da / Num. of mol.: 1 / Mutation: Y181C, C280S, 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: C280S
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-7N1 / 5-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]-4-fluorophenoxy}-7-fluoronaphthalene-2-carbonitrile


Mass: 435.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H15F2N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.8 Å3/Da / Density % sol: 56.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 50 mM MES/Imidazole/HEPES pH 6.0-7.0, 16-20% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.0-7.0

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Data collection

Diffraction
IDMean temperature (K)Crystal-IDSerial crystal experiment
1801N
21001N
Diffraction source
SourceSiteBeamlineTypeIDWavelength (Å)
ROTATING ANODERIGAKU MICROMAX-00711.54187
SYNCHROTRONAPS 24-ID-E20.97918
Detector
TypeIDDetectorDate
DECTRIS PILATUS 200K1PIXELSep 10, 2015
ADSC QUANTUM 3152CCDAug 13, 2015
Radiation
IDProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray2
Radiation wavelength
IDWavelength (Å)Relative weight
11.541871
20.979181
ReflectionResolution: 2.77→41.3802 Å / Num. obs: 32164 / % possible obs: 99.6 % / Redundancy: 3.9 % / CC1/2: 0.99 / Rmerge(I) obs: 0.047 / Rrim(I) all: 0.054 / Net I/σ(I): 19.87
Reflection shell

Diffraction-ID: 2

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.77-2.843.80.5243.623750.8780.6199.81
2.84-2.920.40223030.920.4679
2.92-30.31622280.9550.368
3-3.10.25522040.9690.296
3.1-3.20.1921140.9810.221
3.2-3.310.13620350.9880.158
3.31-3.440.10619710.9930.123
3.44-3.580.0818980.990.096
3.58-3.740.06418250.9960.075
3.74-3.920.05217280.9970.061
3.92-4.130.04316530.9980.05
4.13-4.380.03615800.9980.043
4.38-4.680.03214950.990.037
4.68-5.060.03113510.9980.036
5.06-5.540.0312910.990.035
5.54-6.190.03111530.9980.036
6.19-7.150.029910210.990.034
7.15-8.760.0318870.990.034
8.76-12.390.02568110.0279

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.77→39.92 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.07 / Phase error: 30.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2679 1609 5 %
Rwork0.2402 --
obs0.2416 32158 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.77→39.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7430 0 32 22 7484
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027690
X-RAY DIFFRACTIONf_angle_d0.46110481
X-RAY DIFFRACTIONf_dihedral_angle_d12.8272819
X-RAY DIFFRACTIONf_chiral_restr0.0411146
X-RAY DIFFRACTIONf_plane_restr0.0041326
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.77-2.860.35041460.2982775X-RAY DIFFRACTION100
2.86-2.960.39171460.31942755X-RAY DIFFRACTION100
2.96-3.080.32311450.31862769X-RAY DIFFRACTION100
3.08-3.220.33091450.28152751X-RAY DIFFRACTION100
3.22-3.390.29361450.27172767X-RAY DIFFRACTION100
3.39-3.60.31611460.27952759X-RAY DIFFRACTION99
3.6-3.880.30131450.25172763X-RAY DIFFRACTION99
3.88-4.270.24491460.222761X-RAY DIFFRACTION99
4.27-4.890.22151450.20932783X-RAY DIFFRACTION100
4.89-6.150.26731490.232807X-RAY DIFFRACTION100
6.16-39.920.22031510.20712859X-RAY DIFFRACTION99

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