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- PDB-9mxb: Crystal Structure of WT HIV-1 Reverse Transcriptase in Complex wi... -

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Basic information

Entry
Database: PDB / ID: 9mxb
TitleCrystal Structure of WT HIV-1 Reverse Transcriptase in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy] phenoxy}naphthalene-2-carbonitrile (JLJ648), 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 / 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 / Retrovirus capsid, C-terminal / 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
: / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsHollander, K. / 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)NIH/NAD AI155072 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI186613 United States
CitationJournal: NPJ Drug Discov / Year: 2025
Title: Mechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells.
Authors: Klarissa Hollander / Swapnil C Devarkar / Su Tang / Ritudhwaj Tiwari / Shumeng Ma / Won Gil Lee / Elizabeth Denn / Qiankun Wang / Krasimir A Spasov / Jake A Robbins / Kathleen M Frey / ...Authors: Klarissa Hollander / Swapnil C Devarkar / Su Tang / Ritudhwaj Tiwari / Shumeng Ma / Won Gil Lee / Elizabeth Denn / Qiankun Wang / Krasimir A Spasov / Jake A Robbins / Kathleen M Frey / William L Jorgensen / Yong Xiong / Liang Shan / Karen S Anderson /
Abstract: A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These ...A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These NNRTIs stimulate dimerization of the Gag-Pol polyprotein, resulting in premature HIV-1 protease (PR) dimerization and cleavage of intracellular CARD8. A unique cell-based high-throughput screen was developed to identify potent compounds activating the CARD8 inflammasome through Gag-Pol dimerization. Our in-house library of NNRTIs was evaluated, including a series of catechol diethers, which are potent, nontoxic antivirals. JLJ648 was identified as a promising dual-function antiviral and Gag-Pol dimerizer. Cryo-EM studies of HIV reverse transcriptase p66 bound to JLJ648 revealed populations of homodimers and, surprisingly, a homotetramer. This novel homotetramer structure resembling an 'infinity knot' revealed two JLJ648-bound homodimers forming an extensive interface and nucleated around a dimer of JLJ648 molecules. Structure-guided mutagenesis studies indicate that Gag-Pol homotetramerization may play a critical role in facilitating PR self-cleavage and triggering pyroptosis.
History
DepositionJan 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 17, 2025Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,8238
Polymers114,1092
Non-polymers7146
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5510 Å2
ΔGint-73 kcal/mol
Surface area44730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.074, 69.566, 104.949
Angle α, β, γ (deg.)90.00, 106.08, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 2 molecules AB

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


Mass: 63989.238 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / 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: 50119.465 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag-pol / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03366

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Non-polymers , 4 types, 27 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-A1BTU / 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}naphthalene-2-carbonitrile


Mass: 415.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H17N3O3S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.44 Å3/Da / Density % sol: 64.29 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50 mM Citric Acid pH 5.5, 15% PEG 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, and 5 mM spermine
PH range: 5.0-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.979338 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979338 Å / Relative weight: 1
ReflectionResolution: 2.37→33.63 Å / Num. obs: 63659 / % possible obs: 100 % / Redundancy: 7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.026 / Rrim(I) all: 0.069 / Χ2: 0.91 / Net I/σ(I): 13.9 / Num. measured all: 446532
Reflection shellResolution: 2.37→2.49 Å / % possible obs: 100 % / Redundancy: 7.2 % / Rmerge(I) obs: 2.588 / Num. measured all: 66879 / Num. unique obs: 9286 / CC1/2: 0.493 / Rpim(I) all: 1.026 / Rrim(I) all: 2.786 / Χ2: 0.83 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
Aimless0.7.7data scaling
XDSJun 30, 2023 (BUILT 20230630)data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.37→33.63 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 39.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2747 3135 4.96 %
Rwork0.2529 --
obs0.254 63206 99.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.37→33.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7564 0 43 21 7628
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037838
X-RAY DIFFRACTIONf_angle_d0.53710715
X-RAY DIFFRACTIONf_dihedral_angle_d15.9392828
X-RAY DIFFRACTIONf_chiral_restr0.0431174
X-RAY DIFFRACTIONf_plane_restr0.0041359
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.37-2.40.4881440.45362434X-RAY DIFFRACTION89
2.4-2.440.47721400.4472660X-RAY DIFFRACTION98
2.44-2.490.44691320.40992715X-RAY DIFFRACTION99
2.49-2.530.43051250.39772743X-RAY DIFFRACTION100
2.53-2.580.41241480.38692708X-RAY DIFFRACTION100
2.58-2.630.37011460.37472734X-RAY DIFFRACTION100
2.63-2.690.35991430.34822727X-RAY DIFFRACTION100
2.69-2.750.39011310.34352727X-RAY DIFFRACTION100
2.75-2.820.34771510.342719X-RAY DIFFRACTION100
2.82-2.90.38591340.30912772X-RAY DIFFRACTION100
2.9-2.980.40691460.30692712X-RAY DIFFRACTION100
2.98-3.080.3741580.32562733X-RAY DIFFRACTION100
3.08-3.190.34791120.33262772X-RAY DIFFRACTION100
3.19-3.320.40011450.31812734X-RAY DIFFRACTION100
3.32-3.470.34521390.29582763X-RAY DIFFRACTION100
3.47-3.650.31061460.29442741X-RAY DIFFRACTION100
3.65-3.880.29611380.26792756X-RAY DIFFRACTION100
3.88-4.180.26821460.23592757X-RAY DIFFRACTION100
4.18-4.590.25161540.20692750X-RAY DIFFRACTION100
4.6-5.260.23141590.20722765X-RAY DIFFRACTION100
5.26-6.620.271470.2392789X-RAY DIFFRACTION100
6.62-33.630.17791510.18932860X-RAY DIFFRACTION100

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