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- PDB-6ecl: Crystal Structure of a 1,2,4-Triazole Allosteric RNase H Inhibito... -

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Basic information

Entry
Database: PDB / ID: 6ecl
TitleCrystal Structure of a 1,2,4-Triazole Allosteric RNase H Inhibitor in Complex with HIV Reverse Transcriptase
Components(Reverse transcriptase/ribonuclease H) x 2
KeywordsTRANSFERASE / HIV-1 / REVERSE TRANSCRIPTASE / RNASE H / INHIBITOR
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-T90 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.385 Å
AuthorsKirby, K.A. / Sarafianos, S.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI100890 United States
CitationJournal: To be published
Title: Crystal Structure of a 1,2,4-Triazole Allosteric RNase H Inhibitor in Complex with HIV Reverse Transcriptase
Authors: Kirby, K.A. / Sarafianos, S.G.
History
DepositionAug 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 21, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 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
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_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id

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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)114,6795
Polymers114,2022
Non-polymers4773
Water3,369187
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5530 Å2
ΔGint-40 kcal/mol
Surface area47160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.109, 73.409, 108.584
Angle α, β, γ (deg.)90.000, 100.430, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Reverse transcriptase/ribonuclease H


Mass: 64105.441 Da / Num. of mol.: 1 / Fragment: p66 domain / Mutation: C879S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Plasmid: pET35a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) RIL / References: UniProt: P03366, exoribonuclease H
#2: Protein Reverse transcriptase/ribonuclease H


Mass: 50096.539 Da / Num. of mol.: 1 / Fragment: p51 domain / Mutation: C879S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Plasmid: pET35a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) RIL / References: UniProt: P03366, exoribonuclease H
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-T90 / 1-[4-methoxy-3-[[5-methyl-4-(phenylmethyl)-1,2,4-triazol-3-yl]sulfanylmethyl]phenyl]ethanone


Mass: 367.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N3O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 187 / 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: 2.8 Å3/Da / Density % sol: 56.06 % / Mosaicity: 0.22 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6
Details: PEG 3350, SODIUM POTASSIUM PHOSPHATE, BIS TRIS PROPANE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: NOIR-1 / Detector: CCD / Date: Aug 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.38→19.77 Å / Num. obs: 49173 / % possible obs: 97.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 47.23 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.021 / Rrim(I) all: 0.041 / Net I/σ(I): 19.7 / Num. measured all: 181751
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.38-2.463.30.2139820.9460.1390.25386.7
9.54-19.773.50.0227380.9980.0130.02688.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation8.13 Å19.77 Å
Translation8.13 Å19.77 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.25data scaling
PHASER2.6.1phasing
PHENIX1.10.1refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4G1Q

4g1q


Resolution: 2.385→19.768 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.84
RfactorNum. reflection% reflection
Rfree0.2289 2463 5.02 %
Rwork0.1851 --
obs0.1872 49074 97.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 188.93 Å2 / Biso mean: 69.8504 Å2 / Biso min: 21.08 Å2
Refinement stepCycle: final / Resolution: 2.385→19.768 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7854 0 28 187 8069
Biso mean--70.19 56.72 -
Num. residues----957
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0048102
X-RAY DIFFRACTIONf_angle_d0.611009
X-RAY DIFFRACTIONf_chiral_restr0.0451191
X-RAY DIFFRACTIONf_plane_restr0.0041383
X-RAY DIFFRACTIONf_dihedral_angle_d13.8824878
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3849-2.43060.2855960.2592084218078
2.4306-2.48020.30031420.24192532267496
2.4802-2.5340.25241240.21482581270598
2.534-2.59280.27091380.21462574271298
2.5928-2.65750.27141520.21222594274698
2.6575-2.72920.27481470.21162621276898
2.7292-2.80930.27821610.22422592275398
2.8093-2.89970.28631390.2182599273898
2.8997-3.0030.28431350.21352610274598
3.003-3.12280.30721380.22452609274798
3.1228-3.26430.28161230.2192627275099
3.2643-3.43550.22861310.20372641277299
3.4355-3.64950.2111320.19252626275899
3.6495-3.92930.23881420.17292622276499
3.9293-4.3210.20581240.15982657278199
4.321-4.93770.17011620.15112639280199
4.9377-6.18910.21231330.17342667280099
6.1891-19.76850.19691440.15942736288099
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.27770.9040.11271.3443-0.39340.84260.304-0.35960.19710.8738-0.15160.4115-0.48330.3946-0.13611.0907-0.05830.29960.74270.05980.5615212.414-18.491665.1084
20.05821.3335-0.4989-0.05440.43622.06840.6199-0.1423-0.20550.4599-0.33720.2553-0.04-0.0239-0.22971.0574-0.03030.0760.54460.08340.4869208.0887-28.007960.8446
30.6880.0799-1.6535-0.0764-1.11272.73980.3554-0.25550.04120.1843-0.24770.2014-0.4020.49470.00641.1129-0.18110.14810.6730.05820.4146210.8867-22.182769.7687
41.3392-0.08670.88761.3703-0.43042.83820.1543-0.2332-0.51570.18940.29530.29640.0906-0.3092-0.29690.5041-0.0247-0.04440.40960.15080.488205.8628-32.828939.9515
51.3534-0.88891.09772.221-1.50153.33830.2196-0.0645-0.3729-0.04190.19230.37180.2076-0.2472-0.2490.2269-0.0192-0.02270.2329-0.00530.4237198.7804-23.049317.4909
62.3913-0.96771.27681.59590.03890.359-0.1083-0.2773-0.29680.11930.13020.09340.0834-0.0895-0.04610.20750.00640.07130.42740.06440.3766176.2098-0.6776.5152
72.29610.98640.03982.0482-0.81941.03370.02160.10080.1742-0.2723-0.16530.9264-0.4901-0.36840.07160.33150.05920.00540.4523-0.04870.5959176.4099.8843.8976
82.9036-0.05811.06413.29-0.09212.393-0.0890.05160.20950.3078-0.1207-0.1692-0.26520.34330.07070.4317-0.041-0.04020.36910.03320.3026219.86-5.770936.5021
91.2815-0.10790.74942.1275-0.5691.7404-0.1290.10020.4460.5581-0.0896-0.4777-0.29950.29750.03830.4973-0.1368-0.11980.4270.060.5293224.22967.881833.9225
102.37860.39031.93121.21910.05992.7084-0.22660.24350.36080.1256-0.0818-0.1893-0.3270.24220.20840.2597-0.07030.01930.28930.0390.3276202.790717.233510.0474
111.64170.30851.51032.98090.40931.15410.03250.06430.10380.1707-0.1863-0.064-0.09120.06730.16060.35-0.05340.07290.30160.01980.2885206.50753.285620.2958
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 27 )A-1 - 27
2X-RAY DIFFRACTION2chain 'A' and (resid 28 through 114 )A28 - 114
3X-RAY DIFFRACTION3chain 'A' and (resid 115 through 155 )A115 - 155
4X-RAY DIFFRACTION4chain 'A' and (resid 156 through 297 )A156 - 297
5X-RAY DIFFRACTION5chain 'A' and (resid 298 through 421 )A298 - 421
6X-RAY DIFFRACTION6chain 'A' and (resid 422 through 527 )A422 - 527
7X-RAY DIFFRACTION7chain 'A' and (resid 528 through 554 )A528 - 554
8X-RAY DIFFRACTION8chain 'B' and (resid 5 through 83 )B5 - 83
9X-RAY DIFFRACTION9chain 'B' and (resid 84 through 194 )B84 - 194
10X-RAY DIFFRACTION10chain 'B' and (resid 195 through 363 )B195 - 363
11X-RAY DIFFRACTION11chain 'B' and (resid 364 through 428 )B364 - 428

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