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- PDB-4qag: Structure of a dihydroxycoumarin active-site inhibitor in complex... -

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Basic information

Entry
Database: PDB / ID: 4qag
TitleStructure of a dihydroxycoumarin active-site inhibitor in complex with the RNASE H domain of HIV-1 reverse transcriptase
ComponentsReverse transcriptase/ribonuclease H
KeywordsHYDROLASE/HYDROLASE INHIBITOR / RNASE H INHIBITOR / STRUCTURE-BASED DRUG DESIGN / ACTIVE SITE / TRANSFERASE / DIHYDROXYCOUMARIN ANALOGS / DIHYDROXY-BENZOPYRONE DERIVATIVES / DIVALENT CATION CHELATOR / AIDS / REVERSE TRANSCRIPTASE / PROTEIN-INHIBITOR COMPLEX / HYDROLASE-HYDROLASE INHIBITOR complex
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 / RNA-directed DNA polymerase / establishment of integrated proviral latency / 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 / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / host multivesicular body / viral penetration into host nucleus / 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
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 ...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. / 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 / 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. / Nucleotidyltransferase; domain 5 / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
(7,8-dihydroxy-2-oxo-2H-chromen-4-yl)acetic acid / : / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.712 Å
AuthorsHimmel, D.M. / Ho, W.C. / Arnold, E.
Citation
Journal: J.Mol.Biol. / Year: 2014
Title: Structure of a Dihydroxycoumarin Active-Site Inhibitor in Complex with the RNase H Domain of HIV-1 Reverse Transcriptase and Structure-Activity Analysis of Inhibitor Analogs.
Authors: Himmel, D.M. / Myshakina, N.S. / Ilina, T. / Van Ry, A. / Ho, W.C. / Parniak, M.A. / Arnold, E.
#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 Jr., A.D. / Ryan, K. / Hickey, M.J. / Love, R.A. / Hughes, S.H. / Bergqvist, S. / Arnold, E.
#2: 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. / Wojtak, K. / Bauman, J.D. / Rausch, J.W. / Wilson, J.A. / Beutler, J.A. / Thomas, C.J. / Arnold, E. / Le Grice, S.F.J.
#3: Journal: Proc.Natl.Acad.Sci.USA / Year: 2008
Title: HIGH-RESOLUTION STRUCTURES OF HIV-1 REVERSE TRANSCRIPTASE/TMC278 COMPLEXES: STRATEGIC FLEXIBILITY EXPLAINS POTENCY AGAINST RESISTANCE MUTATIONS
Authors: Das, K. / Bauman, J.D. / Clark Jr., A.D. / Frenkel, Y.V. / Lewi, P.J. / Shatkin, A.J. / Hughes, S.H. / Arnold, E.
#4: Journal: ACS CHEM.BIOL. / Year: 2006
Title: HIV-1 REVERSE TRANSCRIPTASE STRUCTURE WITH RNASE H INHIBITOR DIHYDROXY BENZOYL NAPHTHYL HYDRAZONE BOUND AT A NOVEL SITE
Authors: Himmel, D.M. / Sarafianos, S.G. / Dharmasena, S. / Hossain, M.M. / McCoy-Simandle, K. / Ilina, T. / Clark Jr., A.D. / Knight, J.L. / Julias, J.G. / Clark, P.K. / Krogh-Jespersen, K. / Levy, ...Authors: Himmel, D.M. / Sarafianos, S.G. / Dharmasena, S. / Hossain, M.M. / McCoy-Simandle, K. / Ilina, T. / Clark Jr., A.D. / Knight, J.L. / Julias, J.G. / Clark, P.K. / Krogh-Jespersen, K. / Levy, R.M. / Hughes, S.H. / Parniak, M.A. / Arnold, E.
History
DepositionMay 4, 2014Deposition site: RCSB / Processing site: RCSB
SupersessionJun 4, 2014ID: 4JE2
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2014Group: Database references
Revision 1.2Jul 9, 2014Group: Database references
Revision 1.3Sep 20, 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_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_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_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_auth_asym_id / _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_asym_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)30,1218
Polymers29,4292
Non-polymers6926
Water3,171176
1
A: Reverse transcriptase/ribonuclease H
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,0614
Polymers14,7151
Non-polymers3463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Reverse transcriptase/ribonuclease H
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,0614
Polymers14,7151
Non-polymers3463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-21 kcal/mol
Surface area13860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.164, 51.164, 112.100
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

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Components

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


Mass: 14714.667 Da / Num. of mol.: 2 / Fragment: UNP residues 1024-1156
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Gene: gag-pol / Plasmid: pLysS / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-F95 / (7,8-dihydroxy-2-oxo-2H-chromen-4-yl)acetic acid


Mass: 236.178 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H8O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.88 Å3/Da / Density % sol: 57.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: 100 mM Bicine pH 8.2, 10 mM Manganese Sulfate, 1 mM Sodium Azide, 9% PEG 3350, combined with equal volume of 10 mM Tris pH 8.0, 75 mM NaCl, 20 mg/mL (1.34 mM) RNase H, VAPOR DIFFUSION, ...Details: 100 mM Bicine pH 8.2, 10 mM Manganese Sulfate, 1 mM Sodium Azide, 9% PEG 3350, combined with equal volume of 10 mM Tris pH 8.0, 75 mM NaCl, 20 mg/mL (1.34 mM) RNase H, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 3, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionRedundancy: 7.8 % / Number: 272419 / Rmerge(I) obs: 0.088 / Χ2: 1 / D res high: 1.71 Å / D res low: 40 Å / Num. obs: 34856 / % possible obs: 98.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
3.684010.0881.00417.5
2.923.6810.0821.00110.1
2.552.9210.0851.0048.4
2.322.5510.1011.0038
2.152.3210.1281.0017.6
2.032.1510.1631.0037.2
1.932.0310.2361.0056.1
1.841.9310.3115.3
1.771.8410.4250.9984.2
1.711.7710.4511.0052.9
ReflectionResolution: 1.71→40 Å / Num. all: 35387 / Num. obs: 34856 / % possible obs: 98.5 % / Observed criterion σ(I): -0.4 / Redundancy: 7.8 % / Biso Wilson estimate: 34.341 Å2 / Rmerge(I) obs: 0.088 / Rsym value: 0.088 / Χ2: 1.003 / Net I/σ(I): 27.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
1.71-1.772.90.4512.431741.00589.5
1.77-1.844.20.4253.134350.99897.6
1.84-1.935.30.314.83538199.3
1.93-2.036.40.2366.434881.00599.5
2.03-2.157.20.1639.335311.00399.7
2.15-2.327.60.12811.635531.00199.7
2.32-2.5580.10114.935431.00399.7
2.55-2.928.40.0851835091.00499.8
2.92-3.6810.10.08221.435471.001100
3.68-4017.50.08829.135381.00499.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 38.45 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å14.77 Å
Translation3.5 Å14.77 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.1.4phasing
PHENIX1.8_1066refinement
PDB_EXTRACT3.14data extraction
ADSCQuantumdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3IG1

3ig1


Resolution: 1.712→28.565 Å / SU ML: 0.23 / Isotropic thermal model: ANISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 26.88 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.1901 946 2.72 %RANDOM
Rwork0.1823 ---
all0.1826 34739 --
obs0.1826 34739 98.25 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 159.53 Å2 / Biso mean: 56.6933 Å2 / Biso min: 30.35 Å2
Refine analyzeLuzzati coordinate error free: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.712→28.565 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2076 0 38 176 2290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082158
X-RAY DIFFRACTIONf_angle_d0.9422930
X-RAY DIFFRACTIONf_chiral_restr0.055330
X-RAY DIFFRACTIONf_plane_restr0.003372
X-RAY DIFFRACTIONf_dihedral_angle_d15.122798
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection allNum. reflection obs% reflection obs (%)
1.712-1.80220.44031220.37144420.044564456491
1.8022-1.91510.28471460.273148310.0244977497799
1.9151-2.06290.21331440.205549100.0185054505499
2.0629-2.27040.18221340.173148990.01650335033100
2.2704-2.59880.20321250.178448980.01850235023100
2.5988-3.27340.19071250.193649200.01750455045100
3.2734-28.56910.17031500.162948930.01450435043100

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