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- PDB-8stu: Crystal Structure of HIV-1 Reverse Transcriptase (Y181C, V106A) v... -

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Basic information

Entry
Database: PDB / ID: 8stu
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C, V106A) variant in Complex with 8-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)-4-fluorophenoxy)-6-fluoroindolizine-2-carbonitrile (JLJ578), a non-nucleoside inhibitor
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsVIRAL PROTEIN / Hydrolase / 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-H9Y / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsHollander, K. / 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)114,3894
Polymers113,9412
Non-polymers4492
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5290 Å2
ΔGint-41 kcal/mol
Surface area43980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.611, 73.983, 109.092
Angle α, β, γ (deg.)90.00, 100.90, 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: 63901.152 Da / Num. of mol.: 1 / Mutation: Y181C, V106A, C280S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Gene: gag-pol
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
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 type 1 BH10
Gene: gag-pol
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P03366
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-H9Y / 8-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]-4-fluorophenoxy}-6-fluoroindolizine-2-carbonitrile


Mass: 424.357 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H14F2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.83 Å3/Da / Density % sol: 56.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 50 mM MES pH 6.0, 14% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.0-6.4

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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: 0.92011 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92011 Å / Relative weight: 1
ReflectionResolution: 2.76→29.62 Å / Num. obs: 32676 / % possible obs: 99.4 % / Redundancy: 6.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.056 / Rrim(I) all: 0.107 / Net I/σ(I): 12.8
Reflection shellResolution: 2.76→2.84 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.749 / Mean I/σ(I) obs: 2 / Num. unique obs: 2263 / CC1/2: 0.79 / Rpim(I) all: 0.434 / Rrim(I) all: 0.812 / % possible all: 93.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DTW

6dtw


Resolution: 2.76→29.62 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 31.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2801 1632 5 %0.1
Rwork0.2261 ---
obs0.2288 32666 99.5 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.76→29.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7282 0 32 27 7341
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027546
X-RAY DIFFRACTIONf_angle_d0.50610323
X-RAY DIFFRACTIONf_dihedral_angle_d14.5662699
X-RAY DIFFRACTIONf_chiral_restr0.0411137
X-RAY DIFFRACTIONf_plane_restr0.0041324
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.76-2.850.35171280.29032447X-RAY DIFFRACTION94
2.85-2.940.31831340.26792562X-RAY DIFFRACTION100
2.94-3.040.32341340.28012568X-RAY DIFFRACTION100
3.04-3.160.3661370.27922595X-RAY DIFFRACTION100
3.16-3.310.34871370.27282609X-RAY DIFFRACTION100
3.31-3.480.32211360.25292562X-RAY DIFFRACTION100
3.48-3.70.34861370.25292605X-RAY DIFFRACTION100
3.7-3.980.30341350.23622567X-RAY DIFFRACTION100
3.98-4.380.25081380.20312613X-RAY DIFFRACTION100
4.38-5.020.25791370.20152595X-RAY DIFFRACTION100
5.02-6.310.28911370.22752631X-RAY DIFFRACTION100
6.31-29.620.20941420.19192680X-RAY DIFFRACTION100

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