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- PDB-4h4m: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 4h4m
TitleCrystal Structure of HIV-1 Reverse Transcriptase 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, Exoribonuclease H, p51 RT
  • Reverse transcriptase/ribonuclease H, Exoribonuclease H, p66 RT
KeywordsHydrolase/Hydrolase inhibitor / Polymerase / Transferase / Hydrolase/inhibitor / Hydrolase-Hydrolase inhibitor complex
Function / homology
Function and homology information


: / : / HIV-1 retropepsin / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral penetration into host nucleus ...: / : / HIV-1 retropepsin / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral penetration into host nucleus / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / RNA 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. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / 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. / 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-494 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.85 Å
AuthorsFrey, K.M. / Anderson, K.S.
CitationJournal: J.Am.Chem.Soc. / Year: 2012
Title: Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design.
Authors: Frey, K.M. / Bollini, M. / Mislak, A.C. / Cisneros, J.A. / Gallardo-Macias, R. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionSep 17, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 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, Exoribonuclease H, p66 RT
B: Reverse transcriptase/ribonuclease H, Exoribonuclease H, p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,5354
Polymers114,0292
Non-polymers5062
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5080 Å2
ΔGint-23 kcal/mol
Surface area48690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)225.133, 69.208, 104.138
Angle α, β, γ (deg.)90.000, 106.430, 90.000
Int Tables number5
Space group name H-MC121
DetailsHeterodimer

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Components

#1: Protein Reverse transcriptase/ribonuclease H, Exoribonuclease H, p66 RT / Gag-Pol polyprotein


Mass: 63989.238 Da / Num. of mol.: 1 / Fragment: HIV-1 Reverse Transcriptase, p66 Subunit / Mutation: C280S, K172A, K173A
Source method: isolated from a genetically manipulated source
Details: Genus Name: Lentivirus / Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: Bh10 Isolate / Gene: p66 RT / 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, Exoribonuclease H, p51 RT / Gag-Pol polyprotein


Mass: 50039.488 Da / Num. of mol.: 1 / Fragment: HIV-1 Reverse Transcriptase, p55 Subunit / Mutation: C280S
Source method: isolated from a genetically manipulated source
Details: Genus Name: Lentivirus / Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: Bh10 Isolate / Gene: p51 RT / 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
#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: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 63.95 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20% (w/v) PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine-HCl, 50 mM HEPES 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: Aug 3, 2012 / Details: Monochromator
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: 2.85→36.639 Å / Num. all: 35694 / Num. obs: 35694 / % possible obs: 98.43 % / Observed criterion σ(F): 1.5 / Observed criterion σ(I): 1.5 / Redundancy: 3.8 % / Biso Wilson estimate: 83.42 Å2 / Rmerge(I) obs: 0.099 / Rsym value: 0.097 / Net I/σ(I): 16.6
Reflection shellResolution: 2.85→2.9 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.411 / Mean I/σ(I) obs: 2.7 / Num. unique all: 1780 / Rsym value: 0.546 / % possible all: 98.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Code 1S9E

1s9e


Resolution: 2.85→36.639 Å / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.7415 / SU ML: 0.41 / σ(F): 1.35 / σ(I): 1.35 / Phase error: 32.08 / Stereochemistry target values: Maximum Likelihood (ML)
RfactorNum. reflection% reflectionSelection details
Rfree0.2733 1999 5.6 %Random
Rwork0.2334 ---
all0.2357 35785 --
obs0.2334 35694 98.43 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 268.37 Å2 / Biso mean: 60.2555 Å2 / Biso min: 0.4 Å2
Refinement stepCycle: LAST / Resolution: 2.85→36.639 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7996 0 34 45 8075
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038254
X-RAY DIFFRACTIONf_angle_d0.91211217
X-RAY DIFFRACTIONf_chiral_restr0.0681209
X-RAY DIFFRACTIONf_plane_restr0.0041411
X-RAY DIFFRACTIONf_dihedral_angle_d14.0633136
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection allNum. reflection obs% reflection obs (%)
2.85-2.92120.36421400.319123692509236998
2.9212-3.00020.3531430.318323982541239899
3.0002-3.08840.32511410.300423832524238399
3.0884-3.18810.33981430.27624022545240299
3.1881-3.30190.33351430.277223932536239399
3.3019-3.4340.32981420.267324122554241299
3.434-3.59020.32231440.277824082552240899
3.5902-3.77930.32491430.259324232566242399
3.7793-4.01580.30941440.242224202564242099
4.0158-4.32540.23341450.214624442589244499
4.3254-4.75990.23561420.198324152557241599
4.7599-5.44670.261460.2014244525912445100
5.4467-6.8550.26931460.2374247026162470100
6.855-36.64190.22271370.206423132450231391

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