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- PDB-4rw8: Crystal Structure of HIV-1 Reverse Transcriptase in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4rw8
TitleCrystal Structure of HIV-1 Reverse Transcriptase in complex with (E)-3-(3-chloro-5-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)phenyl)acrylonitrile (JLJ532), a non-nucleoside inhibitor'
Components
  • Reverse transcriptase/ribonuclease H, p51 subunit
  • Reverse transcriptase/ribonuclease H, p66 subunit
KeywordsHydrolase/hydrolase Inhibitor / polymerase / transferase / rnaseH / Hydrolase-hydrolase Inhibitor complex
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
HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / Ribonuclease H-like superfamily/Ribonuclease H / Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. ...HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / Ribonuclease H-like superfamily/Ribonuclease H / 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. / Nucleotidyltransferase; domain 5 / 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 / Alpha-Beta Plaits / Roll / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3X6 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.878 Å
AuthorsFrey, K.M. / Anderson, K.S.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants.
Authors: Frey, K.M. / Puleo, D.E. / Spasov, K.A. / Bollini, M. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionDec 1, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Reverse transcriptase/ribonuclease H, p66 subunit
B: Reverse transcriptase/ribonuclease H, p51 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4393
Polymers114,0292
Non-polymers4101
Water34219
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4950 Å2
ΔGint-27 kcal/mol
Surface area47700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.820, 69.048, 104.337
Angle α, β, γ (deg.)90.000, 106.290, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 63989.238 Da / Num. of mol.: 1 / Mutation: K172A, K173A, C280S
Source method: isolated from a genetically manipulated source
Details: Lentivirus
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Strain: Bh10 isolate / Gene: gag-pol / Plasmid: pcDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Protein Reverse transcriptase/ribonuclease H, p51 subunit / p51 RT


Mass: 50039.488 Da / Num. of mol.: 1 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Details: Lentivirus
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Strain: Bh10 isolate / Gene: gag-pol / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03366, RNA-directed DNA polymerase
#3: Chemical ChemComp-3X6 / (2E)-3-(3-chloro-5-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}phenyl)prop-2-enenitrile


Mass: 409.822 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16ClN3O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O

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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: 3.41 Å3/Da / Density % sol: 63.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 18% (w/v) PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine, and 50 mM citric acid, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 29, 2013 / Details: Monochrometer
RadiationMonochromator: Cryogenically cooled double crystal monochrometer with horizontal focusing sagittal bend second mono crystal with 4:1 magnification ratio and vertically focusing mirror.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.81→50 Å / Num. all: 37560 / Num. obs: 37560 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 83.76 Å2 / Rsym value: 0.088 / Χ2: 2.357 / Net I/σ(I): 9.6
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allRsym valueΧ2Diffraction-ID% possible all
2.81-2.863.217280.5270.713192
2.86-2.913.618800.5380.747199.9
2.91-2.973.818440.4550.786199.9
2.97-3.033.818870.3940.8551100
3.03-3.093.818770.3370.8761100
3.09-3.163.818930.270.9341100
3.16-3.243.818800.2181.1411100
3.24-3.333.818860.1851.1811100
3.33-3.433.818610.1631.3411100
3.43-3.543.818860.1491.7211100
3.54-3.673.818850.1271.9021100
3.67-3.813.818920.1062.1381100
3.81-3.993.818690.12.5751100
3.99-4.23.819040.0913.1721100
4.2-4.463.818850.0863.9121100
4.46-4.83.819050.0784.0781100
4.8-5.293.819070.0743.9541100
5.29-6.053.818920.0743.799199.9
6.05-7.623.719420.0653.8441100
7.62-503.518570.0627.628193.7

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RW6

4rw6


Resolution: 2.878→36.597 Å / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.7431 / SU ML: 0.49 / Cross valid method: Rfree Flag / σ(F): 1.35 / Phase error: 31.97 / Stereochemistry target values: Maximum Likelihood
RfactorNum. reflection% reflectionSelection details
Rfree0.282 1999 5.73 %Random
Rwork0.2422 ---
obs0.2445 34872 99.14 %-
all-34872 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 164.94 Å2 / Biso mean: 74.5605 Å2 / Biso min: 21.4 Å2
Refinement stepCycle: LAST / Resolution: 2.878→36.597 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7882 0 29 19 7930
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038129
X-RAY DIFFRACTIONf_angle_d0.7311049
X-RAY DIFFRACTIONf_chiral_restr0.0561196
X-RAY DIFFRACTIONf_plane_restr0.0031390
X-RAY DIFFRACTIONf_dihedral_angle_d12.173087
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.878-2.95020.41171340.36712197233195
2.9502-3.02990.35171420.330623562498100
3.0299-3.1190.32511430.306523502493100
3.119-3.21970.30421430.28523412484100
3.2197-3.33470.3661440.28523582502100
3.3347-3.46810.33711450.295423892534100
3.4681-3.62580.31831420.302623312473100
3.6258-3.81680.31951440.258723562500100
3.8168-4.05560.28081430.243523692512100
4.0556-4.36830.26391440.221623642508100
4.3683-4.8070.25841430.216523582501100
4.807-5.50060.25811450.215823802525100
5.5006-6.92240.30281470.245924112558100
6.9224-36.60040.22451400.19882313245394

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