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- PDB-5tw3: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 5tw3
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 5-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)-4-fluorophenoxy)-7-fluoro-2-naphthonitrile (JLJ636), a Non-nucleoside Inhibitor
Components
  • HIV-1 REVERSE TRANSCRIPTASE, P51 SUBUNIT
  • HIV-1 REVERSE TRANSCRIPTASE, P66 SUBUNIT
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / Polymerase / reverse transcriptase / HIV / non-nucleoside inhibitor / HYDROLASE-DNA-INHIBITOR complex / 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 / symbiont-mediated suppression of host gene expression / 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 / 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
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 / RNase H type-1 domain profile. / Ribonuclease H domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retroviral matrix protein / Retrovirus capsid, C-terminal / 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-7N1 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.853 Å
AuthorsChan, A.H. / Anderson, K.S.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM049551 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI044616 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM032136 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI122864 United States
CitationJournal: Mol. Pharmacol. / Year: 2017
Title: Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection.
Authors: Kudalkar, S.N. / Beloor, J. / Chan, A.H. / Lee, W.G. / Jorgensen, W.L. / Kumar, P. / Anderson, K.S.
History
DepositionNov 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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: HIV-1 REVERSE TRANSCRIPTASE, P66 SUBUNIT
B: HIV-1 REVERSE TRANSCRIPTASE, P51 SUBUNIT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4884
Polymers114,0292
Non-polymers4602
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5050 Å2
ΔGint-35 kcal/mol
Surface area46480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.445, 69.469, 104.547
Angle α, β, γ (deg.)90.000, 106.040, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein HIV-1 REVERSE TRANSCRIPTASE, P66 SUBUNIT / Pr160Gag-Pol


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 (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: PCDF-2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P03366, HIV-1 retropepsin, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Protein HIV-1 REVERSE TRANSCRIPTASE, P51 SUBUNIT / Pr160Gag-Pol


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 (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: PCDF-2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P03366, HIV-1 retropepsin, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#3: Chemical ChemComp-7N1 / 5-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]-4-fluorophenoxy}-7-fluoronaphthalene-2-carbonitrile


Mass: 435.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H15F2N3O4
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 3.43 Å3/Da / Density % sol: 64.19 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 50 mM MES pH 6.0, 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
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 5, 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: 2.85→41.375 Å / Num. obs: 36173 / % possible obs: 99.4 % / Redundancy: 3.8 % / Biso Wilson estimate: 64.38 Å2 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.041 / Rrim(I) all: 0.081 / Χ2: 1.581 / Net I/av σ(I): 24.167 / Net I/σ(I): 9.9 / Num. measured all: 137490
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.85-2.93.80.510.847199
2.9-2.953.80.4490.882199.1
2.95-3.013.80.3840.921199.1
3.01-3.073.80.3330.935199.3
3.07-3.143.80.2750.95199.2
3.14-3.213.80.2150.972199.3
3.21-3.293.80.1810.975199.4
3.29-3.383.80.1470.983199.3
3.38-3.483.80.1260.988199.3
3.48-3.593.80.1070.99199.5
3.59-3.723.80.0880.992199.4
3.72-3.873.80.0690.995199.5
3.87-4.043.80.0630.995199.7
4.04-4.263.80.0540.997199.6
4.26-4.523.80.050.996199.7
4.52-4.873.80.0530.997199.6
4.87-5.363.80.0590.992199.7
5.36-6.143.70.0660.991199.8
6.14-7.733.70.0440.997199.8
7.73-503.60.0280.997198.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000706edata scaling
PHASER1.9_1692phasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
HKL-2000706edata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WE1

4we1


Resolution: 2.853→41.375 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.41
RfactorNum. reflection% reflection
Rfree0.2725 1809 5 %
Rwork0.227 --
obs0.2292 36160 99.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 147.18 Å2 / Biso mean: 69.2835 Å2 / Biso min: 26.99 Å2
Refinement stepCycle: final / Resolution: 2.853→41.375 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7757 0 33 17 7807
Biso mean--54.9 54.12 -
Num. residues----957
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038003
X-RAY DIFFRACTIONf_angle_d0.63110894
X-RAY DIFFRACTIONf_chiral_restr0.0251191
X-RAY DIFFRACTIONf_plane_restr0.0031367
X-RAY DIFFRACTIONf_dihedral_angle_d11.8482981
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 (%)
2.8528-2.92990.36241370.32422604274199
2.9299-3.01610.37711380.29592617275599
3.0161-3.11350.31611370.29122599273699
3.1135-3.22470.31681380.28292633277199
3.2247-3.35370.31481380.26722616275499
3.3537-3.50630.28571380.25342619275799
3.5063-3.69110.30271390.25182646278599
3.6911-3.92220.27451390.23422636277599
3.9222-4.22470.29321400.216626532793100
4.2247-4.64930.23421400.199526612801100
4.6493-5.32090.24311390.194926512790100
5.3209-6.69920.26661410.230926862827100
6.6992-41.37950.23331450.18492730287599

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