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- PDB-8sts: Crystal Structure of HIV-1 Reverse Transcriptase (Y181C, V106A) v... -

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Basic information

Entry
Database: PDB / ID: 8sts
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C, V106A) varient 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
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsVIRAL PROTEIN / Hydrolase / REVERSE TRANSCRIPTASE / ANTIVIRAL / DRUG DESIGN / HIV-1
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-7N1 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.02 Å
AuthorsHollander, K. / Jorgensen, W.L. / Anderson, K.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIH/NAD AI155072 United States
CitationJournal: Protein Sci. / Year: 2023
Title: Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.
Authors: Hollander, K. / Chan, A.H. / Frey, K.M. / Hunker, O. / Ippolito, J.A. / Spasov, K.A. / Yeh, Y.J. / Jorgensen, W.L. / Ho, Y.C. / Anderson, K.S.
History
DepositionMay 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)229,0278
Polymers228,1084
Non-polymers9194
Water21612
1
C: Reverse transcriptase/ribonuclease H
D: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,5134
Polymers114,0542
Non-polymers4602
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4980 Å2
ΔGint-37 kcal/mol
Surface area44610 Å2
MethodPISA
2
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,5134
Polymers114,0542
Non-polymers4602
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4930 Å2
ΔGint-33 kcal/mol
Surface area43490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.860, 128.260, 133.042
Angle α, β, γ (deg.)90.00, 105.32, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 64014.309 Da / Num. of mol.: 2 / Mutation: Y181C, V106A, C280S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Gene: gag-pol
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (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.: 2 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag-pol
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P03366
#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.: 2 / Source method: obtained synthetically / Formula: C23H15F2N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.24 Å3/Da / Density % sol: 62.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 50 mM HEPES pH 7.0, 20% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.5-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.920105 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.920105 Å / Relative weight: 1
ReflectionResolution: 3.02→128.312 Å / Num. obs: 56957 / % possible obs: 99.6 % / Redundancy: 7.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.121 / Rpim(I) all: 0.049 / Rrim(I) all: 0.13 / Net I/σ(I): 10.3
Reflection shellResolution: 3.02→3.072 Å / Rmerge(I) obs: 2.914 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2810 / CC1/2: 0.375 / Rpim(I) all: 1.15 / Rrim(I) all: 3.134

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1EET

1eet


Resolution: 3.02→38.11 Å / SU ML: 0.59 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 35.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2852 2803 4.94 %0.1
Rwork0.2399 ---
obs0.2422 56739 99.23 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.02→38.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14532 0 66 12 14610
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00114997
X-RAY DIFFRACTIONf_angle_d0.38120516
X-RAY DIFFRACTIONf_dihedral_angle_d13.5415315
X-RAY DIFFRACTIONf_chiral_restr0.0382286
X-RAY DIFFRACTIONf_plane_restr0.0032620
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.02-3.070.44381190.4152581X-RAY DIFFRACTION96
3.07-3.130.41811360.39282681X-RAY DIFFRACTION98
3.13-3.190.40671280.35142686X-RAY DIFFRACTION99
3.19-3.250.38771280.3442700X-RAY DIFFRACTION99
3.25-3.320.33641520.32472703X-RAY DIFFRACTION100
3.32-3.40.36491730.31172632X-RAY DIFFRACTION99
3.4-3.490.34091370.32022682X-RAY DIFFRACTION99
3.49-3.580.38991560.32472686X-RAY DIFFRACTION99
3.58-3.690.33551360.2912679X-RAY DIFFRACTION100
3.69-3.80.33891430.27132720X-RAY DIFFRACTION100
3.8-3.940.36311490.25232694X-RAY DIFFRACTION100
3.94-4.10.28731330.24152716X-RAY DIFFRACTION100
4.1-4.280.3031500.23062691X-RAY DIFFRACTION100
4.28-4.510.28171030.22562737X-RAY DIFFRACTION100
4.51-4.790.25921200.21412719X-RAY DIFFRACTION100
4.79-5.160.25681210.21192738X-RAY DIFFRACTION100
5.16-5.680.27821270.22922727X-RAY DIFFRACTION100
5.68-6.50.2821560.24982723X-RAY DIFFRACTION100
6.5-8.170.26621810.22262711X-RAY DIFFRACTION100
8.17-38.110.20781550.17652730X-RAY DIFFRACTION98

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