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- PDB-6x4d: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 6x4d
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 5-(cyclopropylmethyl)-7-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-8-methyl-2-naphthonitrile (JLJ678), 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 / symbiont-mediated suppression of host gene expression / 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
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 / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / 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. / 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-UO4 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 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)114,6885
Polymers114,0292
Non-polymers6603
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5650 Å2
ΔGint-57 kcal/mol
Surface area46900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.740, 74.270, 108.730
Angle α, β, γ (deg.)90.000, 100.020, 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-UO4 / 5-(cyclopropylmethyl)-7-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}-8-methylnaphthalene-2-carbonitrile


Mass: 467.516 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25N3O4 / 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.: 71 / 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: 2.84 Å3/Da / Density % sol: 56.65 %
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: Aug 16, 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: 2.65→43.367 Å / Num. obs: 37294 / % possible obs: 99.7 % / Redundancy: 3.741 % / Biso Wilson estimate: 55.57 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.063 / Χ2: 0.979 / Net I/σ(I): 19.01 / Num. measured all: 139530 / Scaling rejects: 32
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
2.65-2.723.7940.5952.2110399274327410.7530.69399.9
2.72-2.793.8080.4782.7710167267126700.8440.557100
2.79-2.873.7970.3563.739964262826240.9060.41699.8
2.87-2.963.7870.2834.749457250024970.9360.3399.9
2.96-3.063.7960.2295.799338246424600.9560.26799.8
3.06-3.173.7840.177.648858234523410.9750.19899.8
3.17-3.293.7820.12410.548805233223280.9850.14599.8
3.29-3.423.7930.09114.218254217721760.9920.106100
3.42-3.573.7740.06818.017994212821180.9950.0899.5
3.57-3.753.7610.05122.497676204620410.9970.0699.8
3.75-3.953.750.04226.957163191319100.9980.04999.8
3.95-4.193.7360.03430.826875184218400.9990.0499.9
4.19-4.483.7040.03234.686371172517200.9980.03799.7
4.48-4.843.6470.0337.45780159015850.9980.03599.7
4.84-5.33.6150.02938.385382149814890.9990.03499.4
5.3-5.933.590.02938.884739132413200.9990.03499.7
5.93-6.843.650.02741.164384120712010.9990.03299.5
6.84-8.383.6010.02148.463608101010020.9990.02599.2
8.38-11.853.570.01855.3528207937900.9990.02199.6
11.85-43.3673.3920.01856.214964584410.9990.02196.3

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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: 2.65→43.367 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2582 1865 5 %
Rwork0.2236 35427 -
obs0.2253 37292 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 154.19 Å2 / Biso mean: 62.4375 Å2 / Biso min: 18.27 Å2
Refinement stepCycle: final / Resolution: 2.65→43.367 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7734 0 45 71 7850
Biso mean--60.98 44.59 -
Num. residues----948
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027992
X-RAY DIFFRACTIONf_angle_d0.48310876
X-RAY DIFFRACTIONf_chiral_restr0.0421179
X-RAY DIFFRACTIONf_plane_restr0.0041367
X-RAY DIFFRACTIONf_dihedral_angle_d10.8364784
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.65-2.72160.32691420.30432698100
2.7216-2.80170.38251430.29592728100
2.8017-2.89210.3231420.27122677100
2.8921-2.99550.31251430.27462726100
2.9955-3.11540.31731420.27372698100
3.1154-3.25710.33741420.26752704100
3.2571-3.42880.28631440.25572733100
3.4288-3.64350.31641430.24092707100
3.6435-3.92460.2661430.22212739100
3.9246-4.31930.20051450.1992728100
4.3193-4.94350.21551440.19032749100
4.9435-6.22540.22761440.2147273099
6.2254-43.3670.21881480.1827281099

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