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- PDB-4rw4: Crystal Structure of HIV-1 Reverse Transcriptase (K103N,Y181C) va... -

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Basic information

Entry
Database: PDB / ID: 4rw4
TitleCrystal Structure of HIV-1 Reverse Transcriptase (K103N,Y181C) variant in complex with (E)-3-(3-chloro-5-(4-chloro-2-(2-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)phenyl)acrylonitrile (JLJ494), a Non-nucleoside Inhibitor
Components
  • Reverse transcriptase/ribonuclease H, p51 subunit
  • Reverse transcriptase/ribonuclease H, p66 subunit
KeywordsHydrolase/hydrolase Inhibitor / polymerase / transferase / hydrolase / 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 / DNA integration / host multivesicular body / 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 / DNA integration / host multivesicular body / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / viral penetration into host nucleus / 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 / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / 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-494 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.674 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 1.1Sep 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)114,3983
Polymers113,9542
Non-polymers4441
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5140 Å2
ΔGint-29 kcal/mol
Surface area46570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.672, 74.063, 108.413
Angle α, β, γ (deg.)90.000, 100.580, 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: 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-494 / (2E)-3-(3-chloro-5-{4-chloro-2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}phenyl)prop-2-enenitrile


Mass: 444.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H15Cl2N3O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.83 Å3/Da / Density % sol: 56.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 16-20% (w/v) PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine, and 50 mM citric acid (pH 7.0), 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: 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: 2.63→50 Å / Num. all: 37152 / Num. obs: 37152 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Biso Wilson estimate: 71.38 Å2 / Rsym value: 0.055 / Net I/σ(I): 31.7
Reflection shellResolution: 2.63→2.68 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.1 / Num. unique all: 1845 / Rsym value: 0.543 / % possible all: 99.8

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Processing

Software
NameVersionClassificationNB
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: 2.674→35.523 Å / Occupancy max: 1 / Occupancy min: 0.4 / FOM work R set: 0.7561 / SU ML: 0.4 / σ(F): 1.34 / Phase error: 30.92 / Stereochemistry target values: Maximum Likelihood
RfactorNum. reflection% reflectionSelection details
Rfree0.2777 1773 5 %Random
Rwork0.2309 ---
obs0.2333 35454 97.63 %-
all-35454 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 155.79 Å2 / Biso mean: 67.6082 Å2 / Biso min: 13.49 Å2
Refinement stepCycle: LAST / Resolution: 2.674→35.523 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7715 0 30 12 7757
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037965
X-RAY DIFFRACTIONf_angle_d0.72610830
X-RAY DIFFRACTIONf_chiral_restr0.0541174
X-RAY DIFFRACTIONf_plane_restr0.0031364
X-RAY DIFFRACTIONf_dihedral_angle_d12.4173012
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.674-2.74680.34841220.2952325244788
2.7468-2.82760.36241370.29122588272599
2.8276-2.91880.36081380.2832634277299
2.9188-3.02310.3321370.2862592272999
3.0231-3.1440.31531380.27092624276299
3.144-3.2870.2921380.26482633277199
3.287-3.46020.32771390.25612643278299
3.4602-3.67680.30541380.245426132751100
3.6768-3.96030.25171380.23072633277199
3.9603-4.35820.24261400.21622638277899
4.3582-4.98740.28181390.20042641278099
4.9874-6.27790.24961400.226326582798100
6.2779-35.52610.25241290.20442459258889

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