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- PDB-4rw9: Crystal Structure of HIV-1 Reverse Transcriptase (Y181C) variant ... -

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Basic information

Entry
Database: PDB / ID: 4rw9
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C) variant 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 / 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
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 / 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. / Nucleotidyltransferase; domain 5 / 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 / 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 / FOURIER SYNTHESIS / Resolution: 2.986 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)114,3793
Polymers113,9692
Non-polymers4101
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5130 Å2
ΔGint-30 kcal/mol
Surface area46670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.416, 74.026, 108.102
Angle α, β, γ (deg.)90.000, 99.690, 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: 63929.207 Da / Num. of mol.: 1 / Mutation: K172A, K173A, Y181C, 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

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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: 2.79 Å3/Da / Density % sol: 55.96 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 16-20% (w/v) PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine, and 50 mM citric acid pH 6.0 , 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: Jun 5, 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: 2.98→50 Å / Num. all: 24980 / Num. obs: 24980 / % possible obs: 97.1 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 79.84 Å2 / Rsym value: 0.119 / Χ2: 3.727 / Net I/σ(I): 24.9
Reflection shell
Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.98-3.033.70.56612341.037198.7
3.03-3.093.70.4812861.162198.8
3.09-3.153.80.38912391.105198.8
3.15-3.213.70.34412771.313198.8
3.21-3.283.70.28612471.49198.9
3.28-3.363.70.23612801.784198.6
3.36-3.443.70.2212492.194199.1
3.44-3.533.70.18312792.357198.9
3.53-3.643.70.15512502.689199
3.64-3.753.70.13612633.184199
3.75-3.893.70.12212903.695198.8
3.89-4.043.70.11812644.635198.1
4.04-4.233.70.11112465.345197.6
4.23-4.453.60.10312505.681196.8
4.45-4.733.60.09812276.242195.9
4.73-5.093.60.09212316.138195.9
5.09-5.613.60.08912575.451196.8
5.61-6.423.60.08712835.558198.8
6.42-8.083.50.07912636.186195.6
8.08-503.30.08510659.959179.2

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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
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB Code: 2ZD1

2zd1


Resolution: 2.986→34.806 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7483 / SU ML: 0.47 / Cross valid method: Rfree Flag / σ(F): 1.38 / Phase error: 31.51 / Stereochemistry target values: Maximum Likelihood
RfactorNum. reflection% reflectionSelection details
Rfree0.2804 1249 5 %Random
Rwork0.2318 ---
obs0.2342 24976 96.89 %-
all-24976 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 147.71 Å2 / Biso mean: 56.7567 Å2 / Biso min: 7.75 Å2
Refinement stepCycle: LAST / Resolution: 2.986→34.806 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7716 0 29 0 7745
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037955
X-RAY DIFFRACTIONf_angle_d0.71110813
X-RAY DIFFRACTIONf_chiral_restr0.0531173
X-RAY DIFFRACTIONf_plane_restr0.0031360
X-RAY DIFFRACTIONf_dihedral_angle_d12.4363009
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.986-3.10530.38321360.32542584272097
3.1053-3.24650.38211400.27582673281399
3.2465-3.41760.3521420.26672683282599
3.4176-3.63150.32471410.26192670281199
3.6315-3.91150.28481410.22852678281999
3.9115-4.30450.2681400.21482660280098
4.3045-4.92590.27131380.21522635277396
4.9259-6.20040.26441390.23042649278897
6.2004-34.80860.23141320.21052495262789

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