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- PDB-8u6h: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 8u6h
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 3-(2-(2-(3-acryloyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)-4-chlorophenoxy)-5-chlorobenzonitrile (JLJ744), 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 / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase / RNA stem-loop binding ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase / RNA stem-loop binding / viral penetration into host nucleus / host multivesicular body / 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 / symbiont entry into host cell / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / zinc ion binding
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 / RNase H type-1 domain profile. / Ribonuclease H domain / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / 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
PHOSPHATE ION / Chem-VVE / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 Å
AuthorsPrucha, G. / Carter, Z. / 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: Eur.J.Med.Chem. / Year: 2023
Title: Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase.
Authors: Prucha, G.R. / Henry, S. / Hollander, K. / Carter, Z.J. / Spasov, K.A. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionSep 13, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 15, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact / struct_conn
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)229,1268
Polymers227,9434
Non-polymers1,1834
Water30617
1
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6585
Polymers113,9722
Non-polymers6863
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5310 Å2
ΔGint-34 kcal/mol
Surface area43450 Å2
MethodPISA
2
C: Reverse transcriptase/ribonuclease H
D: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4683
Polymers113,9722
Non-polymers4961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4580 Å2
ΔGint-22 kcal/mol
Surface area46300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)112.404, 73.185, 171.583
Angle α, β, γ (deg.)90.00, 97.51, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Reverse transcriptase/ribonuclease H


Mass: 63932.180 Da / Num. of mol.: 2 / Mutation: C879S, 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
#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 (E. coli) / References: UniProt: P03366
#3: Chemical ChemComp-VVE / 3-chloro-5-{4-chloro-2-[2-(2-oxo-3-propanoyl-2,3-dihydro-1H-benzimidazol-1-yl)ethoxy]phenoxy}benzonitrile


Mass: 496.342 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H19Cl2N3O4
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.07 Å3/Da / Density % sol: 59.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.3
Details: 50 mM Imidazole pH 6.3, 14% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 6.3-8.5

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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: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.99→170.11 Å / Num. obs: 56302 / % possible obs: 99.7 % / Redundancy: 3.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.067 / Rrim(I) all: 0.127 / Net I/σ(I): 8.6
Reflection shellResolution: 2.991→3.043 Å / Rmerge(I) obs: 1.157 / Num. unique obs: 2834 / CC1/2: 0.318 / Rpim(I) all: 1.513 / Rrim(I) all: 1.597

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.99→170.11 Å / Cor.coef. Fo:Fc: 0.898 / Cor.coef. Fo:Fc free: 0.884 / SU B: 22.311 / SU ML: 0.394 / Cross valid method: THROUGHOUT / ESU R Free: 0.441 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.279 2748 4.9 %RANDOM
Rwork0.22 ---
obs0.223 53483 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 94.19 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20.99 Å2
2---0.17 Å20 Å2
3----0.15 Å2
Refinement stepCycle: LAST / Resolution: 2.99→170.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13980 0 78 17 14075
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01114843
X-RAY DIFFRACTIONr_bond_other_d0.0010.01613389
X-RAY DIFFRACTIONr_angle_refined_deg1.371.65120325
X-RAY DIFFRACTIONr_angle_other_deg0.4651.56530801
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.75651883
X-RAY DIFFRACTIONr_dihedral_angle_2_deg8.67536
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.092102215
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0570.22272
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0217145
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023191
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it9.68810.6577565
X-RAY DIFFRACTIONr_mcbond_other9.68810.6577565
X-RAY DIFFRACTIONr_mcangle_it14.89919.1269431
X-RAY DIFFRACTIONr_mcangle_other14.89819.1279432
X-RAY DIFFRACTIONr_scbond_it9.88310.587278
X-RAY DIFFRACTIONr_scbond_other9.88210.587279
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other15.57819.34110893
X-RAY DIFFRACTIONr_long_range_B_refined20.01697.2517049
X-RAY DIFFRACTIONr_long_range_B_other20.01797.2517049
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.99→3.07 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 212 -
Rwork0.348 3874 -
obs--98.27 %

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