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- PDB-2ic3: Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcripta... -

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Basic information

Entry
Database: PDB / ID: 2ic3
TitleCrystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with Nonnucleoside Inhibitor HBY 097
Components
  • Reverse transcriptase/ribonuclease H (p51 RT)
  • Reverse transcriptase/ribonuclease H (p66 RT)
KeywordsTRANSFERASE / RT / NNRTI / NONNUCLEOSIDE INHIBITOR / DRUG RESISTANCE / HIV / AIDS / DRUG DESIGN
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
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. / 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 / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / 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. / Aspartic peptidase domain superfamily / Ribonuclease H 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-HBY / : / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsDas, K. / Arnold, E.
Citation
Journal: J.Mol.Biol. / Year: 2007
Title: Crystal Structures of Clinically Relevant Lys103Asn/Tyr181Cys Double Mutant HIV-1 Reverse Transcriptase in Complexes with ATP and Non-nucleoside Inhibitor HBY 097.
Authors: Das, K. / Sarafianos, S.G. / Clark, A.D. / Boyer, P.L. / Hughes, S.H. / Arnold, E.
#1: Journal: Structure / Year: 1996
Title: Structure of Unliganded HIV-1 Reverse Transcriptase at 2.7 A Resolution: Implications of Conformational Changes for Polymerization and Inhibition Mechanisms
Authors: Hsiou, Y. / Ding, J. / Das, K. / D Clark, A. / Hughes, S.H. / Arnold, E.
#2: Journal: J.Mol.Biol. / Year: 1996
Title: Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant.
Authors: Das, K. / Ding, J. / Hsiou, Y. / Clark, A.D. / Moereels, H. / Koymans, L. / Andries, K. / Pauwels, R. / Janssen, P.A. / Boyer, P.L. / Clark, P. / Smith, R.H. / Kroeger Smith, M.B. / ...Authors: Das, K. / Ding, J. / Hsiou, Y. / Clark, A.D. / Moereels, H. / Koymans, L. / Andries, K. / Pauwels, R. / Janssen, P.A. / Boyer, P.L. / Clark, P. / Smith, R.H. / Kroeger Smith, M.B. / Michejda, C.J. / Hughes, S.H. / Arnold, E.
#3: Journal: J.Mol.Biol. / Year: 1998
Title: Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance.
Authors: Hsiou, Y. / Das, K. / Ding, J. / Clark, A.D. / Kleim, J.P. / Winkler, I. / Riess, G. / Hughes, S.H. / Arnold, E.
#4: Journal: J.Mol.Biol. / Year: 2001
Title: The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.
Authors: Hsiou, Y. / Ding, J. / Das, K. / Clark, A.D. / Boyer, P.L. / Lewi, P. / Janssen, P.A. / Kleim, J.P. / Hughes, S.H. / Arnold, E.
#5: Journal: J.Med.Chem. / Year: 2004
Title: Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent ...Title: Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.
Authors: Das, K. / Clark, A.D. / Lewi, P.J. / Heeres, J. / De Jonge, M.R. / Koymans, L.M. / Vinkers, H.M. / Daeyaert, F. / Ludovici, D.W. / Kukla, M.J. / De Corte, B. / Kavash, R.W. / Ho, C.Y. / Ye, ...Authors: Das, K. / Clark, A.D. / Lewi, P.J. / Heeres, J. / De Jonge, M.R. / Koymans, L.M. / Vinkers, H.M. / Daeyaert, F. / Ludovici, D.W. / Kukla, M.J. / De Corte, B. / Kavash, R.W. / Ho, C.Y. / Ye, H. / Lichtenstein, M.A. / Andries, K. / Pauwels, R. / Boyer, P.L. / Clark, P. / Hughes, S.H. / Janssen, P.A. / Arnold, E.
History
DepositionSep 12, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 19, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Oct 20, 2021Group: Advisory / Database references / Derived calculations
Category: database_2 / pdbx_unobs_or_zero_occ_atoms ...database_2 / pdbx_unobs_or_zero_occ_atoms / 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 / _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_conn.ptnr2_label_seq_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 1.5Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Reverse transcriptase/ribonuclease H (p66 RT)
B: Reverse transcriptase/ribonuclease H (p51 RT)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,7924
Polymers116,3962
Non-polymers3952
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6220 Å2
ΔGint-39 kcal/mol
Surface area49250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)223.210, 67.610, 103.580
Angle α, β, γ (deg.)90.00, 108.39, 90.00
Int Tables number5
Space group name H-MC121
DetailsHETERODIMER of p66 and p51 subunits

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Components

#1: Protein Reverse transcriptase/ribonuclease H (p66 RT)


Mass: 64425.855 Da / Num. of mol.: 1 / Fragment: p66 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Genus: Lentivirus / Species: Human immunodeficiency virus 1 / Strain: BH10 ISOLATE / Gene: pol / Production host: Escherichia coli (E. coli) / References: UniProt: P03366, RNA-directed DNA polymerase
#2: Protein Reverse transcriptase/ribonuclease H (p51 RT)


Mass: 51970.562 Da / Num. of mol.: 1 / Fragment: p51 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 BH10
Genus: Lentivirus / Species: Human immunodeficiency virus 1 / Strain: BH10 ISOLATE / Gene: pol / Production host: Escherichia coli (E. coli) / References: UniProt: P03366, RNA-directed DNA polymerase
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-HBY / (S)-4-ISOPROPOXYCARBONYL-6-METHOXY-3-METHYLTHIOMETHYL-3,4-DIHYDROQUINOXALIN-2(1H)-THIONE / HBY 097


Mass: 340.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H20N2O3S2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 3.22 Å3/Da / Density % sol: 61.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: PEG 8000, BIS_TRIS PROPANE, AMMONIUM SULFATE, GLYCEROL, MNCL2, HBY 097, pH 6.8, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 12, 2000
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→40 Å / Num. obs: 26685 / % possible obs: 90.1 % / Observed criterion σ(I): -1 / Redundancy: 3.4 % / Rmerge(I) obs: 0.046 / Χ2: 1.184 / Net I/σ(I): 24.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
3-3.112.20.28721681.26773.4
3.11-3.232.60.24824541.32684
3.23-3.382.90.19125781.39488.2
3.38-3.563.10.14426631.47190.4
3.56-3.783.30.09926921.52391.2
3.78-4.073.40.0727331.43492.9
4.07-4.483.70.05328571.39696.1
4.48-5.1340.04128891.13397.8
5.13-6.464.20.03329400.84498.3
6.46-4040.02327110.55788.3

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNS1.1refinement
PDB_EXTRACT2data extraction
ADSCQUANTUMdata collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1S6Q

1s6q


Resolution: 3→19.9 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 645411.812 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.31 1258 4.9 %RANDOM
Rwork0.257 ---
obs-25752 86.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 29.852 Å2 / ksol: 0.232 e/Å3
Displacement parametersBiso mean: 87.6 Å2
Baniso -1Baniso -2Baniso -3
1-16.34 Å20 Å245.81 Å2
2---23.8 Å20 Å2
3---7.46 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.57 Å0.44 Å
Luzzati d res low-5 Å
Luzzati sigma a0.73 Å0.63 Å
Refinement stepCycle: LAST / Resolution: 3→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7979 0 23 2 8004
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.013
X-RAY DIFFRACTIONc_angle_deg2
X-RAY DIFFRACTIONc_dihedral_angle_d24.3
X-RAY DIFFRACTIONc_improper_angle_d1.43
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 3→3.19 Å / Rfactor Rfree error: 0.035 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.425 147 4.5 %
Rwork0.364 3153 -
obs-3300 67.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramhby.top
X-RAY DIFFRACTION4hby.parion.top
X-RAY DIFFRACTION5&_1_PARAMETER_INFILE_5&_1_TOPOLOGY_INFILE_5

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