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- PDB-6x4a: Crystal Structure of HIV-1 Reverse Transcriptase (Y181C) Variant ... -

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Basic information

Entry
Database: PDB / ID: 6x4a
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C) Variant in Complex with 5-chloro-7-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-8-methyl-2-naphthonitrile (JLJ651), 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-7AY / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.537 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 1.1Dec 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 1.2Oct 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)114,6095
Polymers113,9692
Non-polymers6403
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5750 Å2
ΔGint-59 kcal/mol
Surface area46450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.769, 73.976, 107.899
Angle α, β, γ (deg.)90.000, 100.050, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-720-

HOH

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Components

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


Mass: 63929.207 Da / Num. of mol.: 1 / Mutation: C280S, K172A, K173A, Y181C
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-7AY / 5-chloro-7-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-8-methyl-2-naphthonitrile / JLJ651


Mass: 447.870 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 2.79 Å3/Da / Density % sol: 55.9 % / Mosaicity: 0.848 °
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: Nov 15, 2015
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.53→50 Å / Num. obs: 41537 / % possible obs: 99.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 57.22 Å2 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.034 / Rrim(I) all: 0.066 / Χ2: 2.383 / Net I/σ(I): 16.5 / Num. measured all: 153854
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.53-2.573.70.50820420.7890.3040.5931.53499.6
2.57-2.623.70.42820570.8510.2570.51.57999.4
2.62-2.673.70.37520590.8990.2250.4381.642100
2.67-2.733.70.32120720.9150.1940.3761.67899.6
2.73-2.783.70.25720650.9430.1550.3011.71899.9
2.78-2.853.70.20820900.9650.1250.2441.76699.9
2.85-2.923.70.17120310.9730.1020.21.85100
2.92-33.70.14620930.9810.0870.1711.88399.9
3-3.093.70.12520520.9840.0750.1461.985100
3.09-3.193.70.09920930.990.0590.1162.04199.9
3.19-3.33.80.07720530.9920.0460.092.07499.8
3.3-3.433.80.06620800.9940.040.0782.13699.8
3.43-3.593.80.05720640.9950.0340.0662.1699.9
3.59-3.783.80.04820840.9970.0290.0562.103100
3.78-4.023.80.04520940.9960.0270.0522.133100
4.02-4.333.80.04720820.9960.0280.0552.732100
4.33-4.763.70.05520910.9930.0330.0644.221100
4.76-5.453.70.06421080.9910.0380.0746.064100
5.45-6.863.60.0421210.9950.0240.0473.026100
6.86-503.60.02221060.9990.0140.0263.18397

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TER

5ter


Resolution: 2.537→38.128 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2685 2000 4.82 %
Rwork0.2317 39528 -
obs0.2335 41528 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 146.54 Å2 / Biso mean: 73.6264 Å2 / Biso min: 28.45 Å2
Refinement stepCycle: final / Resolution: 2.537→38.128 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7732 0 42 44 7818
Biso mean--69.33 54.65 -
Num. residues----948
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037985
X-RAY DIFFRACTIONf_angle_d0.61110864
X-RAY DIFFRACTIONf_chiral_restr0.0241178
X-RAY DIFFRACTIONf_plane_restr0.0031366
X-RAY DIFFRACTIONf_dihedral_angle_d11.442994
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.5375-2.60090.39851340.3133265195
2.6009-2.67120.35141430.30242824100
2.6712-2.74980.34871420.292816100
2.7498-2.83850.31921440.29132838100
2.8385-2.93990.31811410.282796100
2.9399-3.05760.3061450.27992862100
3.0576-3.19670.33031430.27462815100
3.1967-3.36510.32721420.26782817100
3.3651-3.57580.3361430.26682822100
3.5758-3.85170.30271450.24152857100
3.8517-4.23880.22911430.20912828100
4.2388-4.85110.21351440.19542853100
4.8511-6.10790.22871450.20982870100
6.1079-38.1280.21741460.1868287998

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