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- PDB-3qlh: HIV-1 Reverse Transcriptase in Complex with Manicol at the RNase ... -

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Basic information

Entry
Database: PDB / ID: 3qlh
TitleHIV-1 Reverse Transcriptase in Complex with Manicol at the RNase H Active Site and TMC278 (Rilpivirine) at the NNRTI Binding Pocket
Components(reverse transcriptase/ribonuclease ...) x 2
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / RNase H Inhibitor / structure-based drug design / tropolone derivatives / divalent cation chelator / Non-nucleoside RT Inhibitor / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


HIV-1 retropepsin / 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 ...HIV-1 retropepsin / 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 / host cell / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / symbiont-mediated suppression of host gene expression / 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 / 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. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / 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. / 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-MNK / Chem-T27 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsHimmel, D.M. / Wojtak, K. / Bauman, J.D. / Arnold, E.
Citation
Journal: J.Med.Chem. / Year: 2011
Title: Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.
Authors: Chung, S. / Himmel, D.M. / Jiang, J.K. / Wojtak, K. / Bauman, J.D. / Rausch, J.W. / Wilson, J.A. / Beutler, J.A. / Thomas, C.J. / Arnold, E. / Le Grice, S.F.
#1: Journal: Structure / Year: 2009
Title: Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.
Authors: Himmel, D.M. / Maegley, K.A. / Pauly, T.A. / Bauman, J.D. / Das, K. / Dharia, C. / Clark, A.D. / Ryan, K. / Hickey, M.J. / Love, R.A. / Hughes, S.H. / Bergqvist, S. / Arnold, E.
#2: Journal: Nucleic Acids Res. / Year: 2008
Title: Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design.
Authors: Bauman, J.D. / Das, K. / Ho, W.C. / Baweja, M. / Himmel, D.M. / Clark, A.D. / Oren, D.A. / Boyer, P.L. / Hughes, S.H. / Shatkin, A.J. / Arnold, E.
#3: Journal: To be Published
Title: Sensitivity of Xenotropic Murine Leukemia Virus-Related Retrovirus Reverse Transcriptase-Associated Ribonuculease H to alpha-Hydroxytropolone Inhibitors
Authors: Chung, S. / Himmel, D.M. / Jiang, J. / Scarth, B. / Wang, Y. / Rausch, J.W. / Lee, K. / KewalRamani, V. / Arnold, E. / Gotte, M. / Beutler, J.A. / Thomas, C.R. / Le Grice, S.F.J.
History
DepositionFeb 2, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 21, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 18, 2012Group: Non-polymer description
Revision 1.2Feb 27, 2013Group: Database references
Revision 1.3Jun 17, 2015Group: Non-polymer description
Revision 1.4Jan 24, 2018Group: Database references / Category: citation_author / Item: _citation_author.name
Revision 1.5Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / entity_src_nat / Item: _entity.details

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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: reverse transcriptase/ribonuclease H
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,1968
Polymers113,3332
Non-polymers8636
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5930 Å2
ΔGint-36 kcal/mol
Surface area47360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.926, 72.978, 108.377
Angle α, β, γ (deg.)90.000, 101.110, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Reverse transcriptase/ribonuclease ... , 2 types, 2 molecules AB

#1: Protein reverse transcriptase/ribonuclease H / p66 RT


Mass: 63800.984 Da / Num. of mol.: 1 / Fragment: P66 (UNP residues 600-1153)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Gene: gag-pol, POL / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus-RIL
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H
#2: Protein reverse transcriptase/ribonuclease H / p51 RT


Mass: 49531.871 Da / Num. of mol.: 1 / Fragment: P51 (UNP residues 605-1027)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Gene: gag-pol, POL / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus-RIL
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase

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Non-polymers , 6 types, 109 molecules

#3: Chemical ChemComp-MNK / (2S)-5,7-dihydroxy-9-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-6H-benzo[7]annulen-6-one / Manicol


Mass: 246.302 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H18O3 / Details: Extracted from the root bark of this Guyanan tree.
#4: Chemical ChemComp-T27 / 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile / Rilpivirine


Mass: 366.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N6 / Comment: medication, inhibitor*YM
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / TMC278 / Rilpilvirine


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 2.81 Å3/Da / Density % sol: 56.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: Protein solution (20 mg/mL in 9.2 mM Tris pH 8.0, 68.7 mM NaCl, 3.6 mM manganese sulfate, 0.7 mM TCEP, 0.9 mM Manicol, 0.7 mM TMC278, 0.27% BOG, 7% DMSO) Mother Liquor (50 mM HEPES pH 7.5, ...Details: Protein solution (20 mg/mL in 9.2 mM Tris pH 8.0, 68.7 mM NaCl, 3.6 mM manganese sulfate, 0.7 mM TCEP, 0.9 mM Manicol, 0.7 mM TMC278, 0.27% BOG, 7% DMSO) Mother Liquor (50 mM HEPES pH 7.5, 100 mM ammonium sulfate, 15 m manganese sulfate, 10 mM spermine, 5 mM TCEP, 11% PEG8000) Cryoprotectant (50 mM HEPES pH 7.5, 50 mM NaCl, 100 mM ammonium sulfate, 15 mM manganese sulfate, 10 mM spermine, 0.69 mM Manicol, 0.34 mM TMC278, 15% PEG8000, 5% PEG400, 10% DMSO, 11% ethylene glycol, 6.5% trimethylamine N-oxide), flash-cooled in LN2, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 7, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→45 Å / Num. all: 35016 / Num. obs: 34841 / % possible obs: 99.5 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.2 % / Biso Wilson estimate: 58.8 Å2 / Rmerge(I) obs: 0.063 / Χ2: 1.029 / Net I/σ(I): 16.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible allMean I/σ(I) obs
2.7-2.753.80.70717241.40199
2.75-2.84.20.60117531.08999.8
2.8-2.854.20.4917201.19199.9
2.85-2.914.20.38717320.9499.7
2.91-2.974.20.30617520.86999.9
2.97-3.045.90.24817300.97799.8
3.04-3.127.90.19617370.93399.8
3.12-3.27.90.16617460.99199.8
3.2-3.37.80.13917411.07899.9
3.3-3.47.70.11417101.04999.9
3.4-3.527.50.117341.14699.9
3.52-3.667.30.08317641.08299.9
3.66-3.8370.07117491.056100
3.83-4.036.90.0617480.9999.8
4.03-4.296.60.05217571.0299.9
4.29-4.626.40.0517370.97199.9
4.62-5.086.20.04917650.94699.9
5.08-5.816.30.04917530.95199.8
5.81-7.326.10.04617861.0899.4
7.32-455.30.03317030.96593.3
2.7-456.20.0633484199.516.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 39.41 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5 Å14.94 Å
Translation5 Å14.94 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.1.4phasing
CNS1.1refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ZD1

2zd1


Resolution: 2.7→43.21 Å / Rfactor Rfree error: 0.008 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8094 / Data cutoff high absF: 369453 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2514 995 3 %RANDOM
Rwork0.2314 ---
all0.232 34773 --
obs0.232 33315 95.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.3762 Å2 / ksol: 0.3036 e/Å3
Displacement parametersBiso max: 163.52 Å2 / Biso mean: 76.1459 Å2 / Biso min: 18.01 Å2
Baniso -1Baniso -2Baniso -3
1--6.52 Å20 Å2-0.64 Å2
2---0.61 Å20 Å2
3---7.13 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.44 Å0.36 Å
Luzzati d res low-5 Å
Luzzati sigma a0.49 Å0.36 Å
Refinement stepCycle: LAST / Resolution: 2.7→43.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7885 0 56 103 8044
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.246
X-RAY DIFFRACTIONc_dihedral_angle_d25.4
X-RAY DIFFRACTIONc_improper_angle_d1.15
X-RAY DIFFRACTIONc_mcbond_it4.71.5
X-RAY DIFFRACTIONc_mcangle_it6.972
X-RAY DIFFRACTIONc_scbond_it6.612
X-RAY DIFFRACTIONc_scangle_it8.792.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection allNum. reflection obsTotal num. of bins used
2.7-2.750.3163470.332314430.04611490149019
2.75-2.80.4313510.324715210.06041572157219
2.8-2.860.3975440.321515420.05991586158619
2.86-2.920.3213500.303616250.04541675167519
2.92-2.990.3863490.29716120.05521661166119
2.99-3.060.3633490.31416650.05191714171419
3.06-3.150.3611540.290617140.04911768176819
3.15-3.240.2853660.26117260.03511792179219
3.24-3.340.2972460.234917810.04381827182719
3.34-3.460.3052540.250717580.04151812181219
3.46-3.60.2683480.234717590.03871807180719
3.6-3.770.2639490.235417670.03771816181619
3.77-3.960.2371530.210217470.03261800180019
3.96-4.210.2425500.197817920.03431842184219
4.21-4.540.1865570.190317830.02471840184019
4.54-4.990.187600.19917790.02411839183919
4.99-5.710.1992620.212217780.02531840184019
5.71-7.20.2927510.247917990.0411850185019
7.2-450.22145530.226647480.0299489717846
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2ion.paramion.top
X-RAY DIFFRACTION3water.paramwater.top
X-RAY DIFFRACTION4allprosth2.parallprosth2.top

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