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- PDB-6x4e: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 6x4e
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with methyl 2-(6-cyano-3-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-4-methylnaphthalen-1-yl)acetate (JLJ681), a Non-nucleoside Inhibitor
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / Polymerase / reverse transcriptase / non-nucleoside inhibitor / 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
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 ...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. / 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 / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Chem-UMV / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsChan, A.H. / Duong, V.N. / Ippolito, J.A. / Jorgensen, W.L. / Anderson, K.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM49551 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI155072 United States
CitationJournal: Protein Sci. / Year: 2020
Title: Structural investigation of 2-naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site.
Authors: Duong, V.N. / Ippolito, J.A. / Chan, A.H. / Lee, W.G. / Spasov, K.A. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionMay 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Data collection / Category: reflns_shell / Item: _reflns_shell.percent_possible_all
Revision 1.2Dec 16, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,8026
Polymers114,0292
Non-polymers7744
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5910 Å2
ΔGint-74 kcal/mol
Surface area46440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.730, 74.080, 108.390
Angle α, β, γ (deg.)90.000, 99.920, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Reverse transcriptase/ribonuclease H / p66 RT


Mass: 63989.238 Da / Num. of mol.: 1 / Mutation: C280S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B
Gene: gag-pol / Plasmid: PCDF-2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H
#2: Protein p51 RT


Mass: 50039.488 Da / Num. of mol.: 1 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B
Gene: gag-pol / Plasmid: PCDF-2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03366
#3: Chemical ChemComp-UMV / methyl (6-cyano-3-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}-4-methylnaphthalen-1-yl)acetate


Mass: 485.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H23N3O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.82 Å3/Da / Density % sol: 56.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 50 mM imidazole pH 6.5, 18% PEG 8,000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 14, 2016
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.6→43.335 Å / Num. obs: 39245 / % possible obs: 99.7 % / Redundancy: 3.735 % / Biso Wilson estimate: 51.23 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.063 / Χ2: 1 / Net I/σ(I): 20.16 / Num. measured all: 146585 / Scaling rejects: 16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.6-2.673.7650.6142.4110731286128500.780.71799.6
2.67-2.743.7610.4953.0110692285228430.8170.57899.7
2.74-2.823.7950.3633.8910333273327230.8950.42299.6
2.82-2.913.7950.2815.0910080265926560.9320.32799.9
2.91-33.8020.2116.529790257425750.9630.246100
3-3.113.7960.1747.999516250925070.9730.20299.9
3.11-3.223.7960.12710.769187242424200.9840.14899.8
3.22-3.363.7830.08814.858781232723210.9920.10399.7
3.36-3.513.6620.07118.288016220421890.9940.08399.3
3.51-3.683.7030.05323.227924215221400.9970.06299.4
3.68-3.883.6990.04128.47613206420580.9980.04899.7
3.88-4.113.6420.03433.36850189318810.9990.0499.4
4.11-4.393.7270.02937.836786182618210.9990.03499.7
4.39-4.753.7030.02540.566258169116900.9990.0399.9
4.75-5.23.6870.02641.795726155115530.9990.03100
5.2-5.813.620.02740.155050140213950.9990.03199.5
5.81-6.713.690.02642.074653126312610.9990.0399.8
6.71-8.223.6470.0250.083920107810750.9990.02399.7
8.22-11.633.6880.01760.1530548288280.9990.019100
11.63-43.3353.540.01562.1516254804590.9990.01895.6

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TER

5ter


Resolution: 2.6→43.335 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2594 1961 5 %
Rwork0.2263 37275 -
obs0.2279 39236 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 143.6 Å2 / Biso mean: 59.8647 Å2 / Biso min: 20.88 Å2
Refinement stepCycle: final / Resolution: 2.6→43.335 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7734 0 51 27 7812
Biso mean--60.96 38.27 -
Num. residues----948
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027996
X-RAY DIFFRACTIONf_angle_d0.50310881
X-RAY DIFFRACTIONf_chiral_restr0.0421178
X-RAY DIFFRACTIONf_plane_restr0.0031368
X-RAY DIFFRACTIONf_dihedral_angle_d10.984782
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.6-2.66490.33421390.31352632100
2.6649-2.7370.33091390.29492658100
2.737-2.81750.33451380.28322618100
2.8175-2.90840.28721390.27142652100
2.9084-3.01240.35231410.27812672100
3.0124-3.13290.33151390.27662643100
3.1329-3.27550.33351400.26652664100
3.2755-3.44810.28561390.2595263499
3.4481-3.6640.24361380.23932642100
3.664-3.94680.27191400.2189265099
3.9468-4.34360.21291410.19782683100
4.3436-4.97130.21771420.19042691100
4.9713-6.26040.24161410.21122689100
6.2604-43.3350.21011450.1812274799

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