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

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Basic information

Entry
Database: PDB / ID: 8stt
TitleCrystal Structure of HIV-1 Reverse Transcriptase (Y181C, V106A) varient in Complex with 8-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)indolizine-2-carbonitrile (JLJ555), a non-nucleoside inhibitor
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsVIRAL PROTEIN / 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 / 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
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 / 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. / 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 / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Chem-29T / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.62 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
A: Reverse transcriptase/ribonuclease H
B: p51 RT
C: Reverse transcriptase/ribonuclease H
D: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,9338
Polymers228,1084
Non-polymers8254
Water1,15364
1
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4664
Polymers114,0542
Non-polymers4132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5150 Å2
ΔGint-34 kcal/mol
Surface area44020 Å2
MethodPISA
2
C: Reverse transcriptase/ribonuclease H
D: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4664
Polymers114,0542
Non-polymers4132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4810 Å2
ΔGint-29 kcal/mol
Surface area44840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.695, 73.006, 170.474
Angle α, β, γ (deg.)90.00, 97.60, 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: C879S, Y181C, V106A, 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 (E. coli)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Protein p51 RT


Mass: 50039.488 Da / Num. of mol.: 2 / Mutation: C879S
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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-29T / 8-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}indolizine-2-carbonitrile


Mass: 388.376 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H16N4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 3.02 Å3/Da / Density % sol: 59.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 50 mM MES pH 6.0, 14% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.0-7.0

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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: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 19, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.62→110.71 Å / Num. obs: 81572 / % possible obs: 99.6 % / Redundancy: 3.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.057 / Rrim(I) all: 0.108 / Χ2: 0.48 / Net I/σ(I): 5.1 / Num. measured all: 289932
Reflection shellResolution: 2.62→2.77 Å / % possible obs: 99.6 % / Redundancy: 3.7 % / Rmerge(I) obs: 1.503 / Num. measured all: 43930 / Num. unique obs: 11839 / CC1/2: 0.401 / Rpim(I) all: 0.905 / Rrim(I) all: 1.758 / Χ2: 0.46 / Net I/σ(I) obs: 0.6

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 8STS

8sts


Resolution: 2.62→54.79 Å / SU ML: 0.54 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2911 4011 4.94 %
Rwork0.2633 --
obs0.2647 81226 99.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.62→54.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14709 0 60 64 14833
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00415235
X-RAY DIFFRACTIONf_angle_d0.64320828
X-RAY DIFFRACTIONf_dihedral_angle_d15.645479
X-RAY DIFFRACTIONf_chiral_restr0.0442304
X-RAY DIFFRACTIONf_plane_restr0.0052672
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.62-2.660.40991090.38652506X-RAY DIFFRACTION94
2.66-2.690.38831300.37472600X-RAY DIFFRACTION97
2.69-2.720.38461230.36152645X-RAY DIFFRACTION98
2.72-2.760.39421430.33992591X-RAY DIFFRACTION100
2.76-2.80.33881470.33582707X-RAY DIFFRACTION100
2.8-2.840.38251560.32592627X-RAY DIFFRACTION99
2.84-2.880.32811340.31762624X-RAY DIFFRACTION100
2.88-2.920.35611450.3242693X-RAY DIFFRACTION99
2.92-2.970.32661220.32622639X-RAY DIFFRACTION100
2.97-3.020.39281410.32652697X-RAY DIFFRACTION100
3.02-3.080.37951380.34632642X-RAY DIFFRACTION99
3.08-3.140.36491510.34572633X-RAY DIFFRACTION100
3.14-3.20.42161570.35242677X-RAY DIFFRACTION100
3.2-3.270.41361400.33892649X-RAY DIFFRACTION100
3.27-3.350.39461550.32792666X-RAY DIFFRACTION100
3.35-3.430.36821210.31042659X-RAY DIFFRACTION100
3.43-3.520.3531460.31152671X-RAY DIFFRACTION100
3.52-3.630.34821200.30682694X-RAY DIFFRACTION99
3.63-3.740.32731400.28952665X-RAY DIFFRACTION99
3.74-3.880.32541380.28382664X-RAY DIFFRACTION99
3.88-4.030.30321180.26242689X-RAY DIFFRACTION99
4.03-4.210.2921370.26282657X-RAY DIFFRACTION99
4.21-4.440.24771360.23132700X-RAY DIFFRACTION100
4.44-4.710.25551340.23062688X-RAY DIFFRACTION100
4.71-5.080.25671590.22752658X-RAY DIFFRACTION99
5.08-5.590.29921320.24052722X-RAY DIFFRACTION99
5.59-6.40.281600.24962669X-RAY DIFFRACTION100
6.4-8.050.22371380.22762747X-RAY DIFFRACTION100
8.06-54.790.17971410.1832736X-RAY DIFFRACTION97

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