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- PDB-4rw7: Crystal Structure of HIV-1 Reverse Transcriptase (K103N, Y181C) v... -

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Basic information

Entry
Database: PDB / ID: 4rw7
TitleCrystal Structure of HIV-1 Reverse Transcriptase (K103N, 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-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 / FOURIER SYNTHESIS / Resolution: 3.014 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)114,3633
Polymers113,9542
Non-polymers4101
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5120 Å2
ΔGint-30 kcal/mol
Surface area46870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.953, 73.874, 108.457
Angle α, β, γ (deg.)90.000, 99.870, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 63914.129 Da / Num. of mol.: 1 / Mutation: K103N, 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: 2.8 Å3/Da / Density % sol: 56.14 %
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: 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: 3.01→50 Å / Num. all: 25032 / Num. obs: 25032 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 85.77 Å2 / Rsym value: 0.122 / Χ2: 6.289 / Net I/σ(I): 32.2
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allRsym valueΧ2Diffraction-ID% possible all
3.01-3.063.812610.4881.361100
3.06-3.123.812350.4361.471100
3.12-3.183.812510.371.758199.8
3.18-3.243.812130.3292.069199.8
3.24-3.313.812720.2872.5411100
3.31-3.393.812390.2522.787199.9
3.39-3.473.812400.3445.8271100
3.47-3.573.812500.2034.0271100
3.57-3.673.812600.2316.889199.9
3.67-3.793.812320.1776.0511100
3.79-3.933.812420.2219.819199.9
3.93-4.083.712570.1548.3991100
4.08-4.273.812630.1439.1831100
4.27-4.53.812520.13710.9321100
4.5-4.783.712480.12710.8781100
4.78-5.153.712690.11710.0681100
5.15-5.663.712660.1159.5471100
5.66-6.483.712720.1027.6761100
6.48-8.163.612840.0766.8621100
8.16-503.512260.0677.941193.4

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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: 4H4M

4h4m


Resolution: 3.014→34.965 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7737 / SU ML: 0.45 / Cross valid method: Rfree Flag / σ(F): 1.34 / Phase error: 29.28 / Stereochemistry target values: Maximum Likelihood
RfactorNum. reflection% reflectionSelection details
Rfree0.2657 2000 7.99 %Random
Rwork0.2289 ---
obs0.2319 25024 99.38 %-
all-25024 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 159.79 Å2 / Biso mean: 60.8217 Å2 / Biso min: 6.84 Å2
Refinement stepCycle: LAST / Resolution: 3.014→34.965 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7715 0 29 0 7744
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037954
X-RAY DIFFRACTIONf_angle_d0.72410813
X-RAY DIFFRACTIONf_chiral_restr0.0541173
X-RAY DIFFRACTIONf_plane_restr0.0041361
X-RAY DIFFRACTIONf_dihedral_angle_d12.4773007
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 (%)
3.014-3.08920.33221370.2951576171396
3.0892-3.17270.3861430.271216451788100
3.1727-3.2660.31531420.276616381780100
3.266-3.37130.33281420.265216361778100
3.3713-3.49170.3291410.273616281769100
3.4917-3.63140.32051440.255116491793100
3.6314-3.79650.29171420.249716361778100
3.7965-3.99640.29041440.235916501794100
3.9964-4.24630.28641430.229216651808100
4.2463-4.57360.25581440.214816541798100
4.5736-5.03260.25731440.205516561800100
5.0326-5.7580.22591450.220116661811100
5.758-7.24390.2971450.240416791824100
7.2439-34.96730.19041440.19541646179096

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