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- PDB-4g1q: Crystal structure of HIV-1 reverse transcriptase (RT) in complex ... -

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Basic information

Entry
Database: PDB / ID: 4g1q
TitleCrystal structure of HIV-1 reverse transcriptase (RT) in complex with Rilpivirine (TMC278, Edurant), a non-nucleoside rt-inhibiting drug
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / P51/P66 / HETERO DIMER / NNRTI / NONNUCLEOSIDE INHIBITOR / AIDS / HIV / R278474 / DIARYLPYRIMIDINE / DAPY / DNA RECOMBINATION / RNA-DIRECTED DNA POLYMERASE / DNA POLYMERASE / ENDONUCLEASE / HYDROLASE / MULTIFUNCTIONAL ENZYME / 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 / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / RNA 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 / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / 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-T27 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 Å
AuthorsBauman, J.D. / Patel, D. / Das, K. / Arnold, E.
Citation
Journal: Nat Chem / Year: 2013
Title: Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
Authors: Kuroda, D.G. / Bauman, J.D. / Challa, J.R. / Patel, D. / Troxler, T. / Das, K. / Arnold, E. / Hochstrasser, R.M.
#1: 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, A.D. / Frenkel, Y.V. / Lewi, P.J. / Shatkin, A.J. / Hughes, S.H. / Arnold, E.
#2: Journal: Nat.Struct.Mol.Biol. / Year: 2012
Title: HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism.
Authors: Das, K. / Martinez, S.E. / Bauman, J.D. / Arnold, E.
#3: 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.
#4: 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.
#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. / De Bethune, M.P. / Boyer, P.L. / Clark, P. / Hughes, S.H. / Janssen, P.A. / Arnold, E.
History
DepositionJul 11, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2013Group: Database references
Revision 1.2Jun 17, 2015Group: Non-polymer description
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Sep 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

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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: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,30615
Polymers114,0292
Non-polymers1,27713
Water14,844824
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5170 Å2
ΔGint-30 kcal/mol
Surface area47100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.713, 72.517, 109.514
Angle α, β, γ (deg.)90.00, 100.84, 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 / Fragment: P66, UNP residues 600-1154 / Mutation: K172A, K173A, C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: BH10 ISOLATE / Gene: gag-pol / Plasmid: PRT52A / Production host: Escherichia coli (E. coli)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H
#2: Protein p51 RT


Mass: 50039.488 Da / Num. of mol.: 1 / Fragment: P51, UNP residues 600-1027 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: BH10 ISOLATE / Gene: gag-pol / Plasmid: PRT52A / Production host: Escherichia coli (E. coli)
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H

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Non-polymers , 5 types, 837 molecules

#3: Chemical ChemComp-T27 / 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile / Rilpivirine / Rilpivirine


Mass: 366.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N6 / Comment: medication, inhibitor*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 824 / 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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.8
Details: PEG 8000, AMMONIUM SULFATE, MGCL2,IMIDAZOLE, pH 6.8, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 12, 2009
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 193097 / % possible obs: 96.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -1 / Redundancy: 6.2 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 20
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 4 % / Rmerge(I) obs: 0.797 / Mean I/σ(I) obs: 1.6 / Num. unique all: 9311 / % possible all: 93.3

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHENIXmodel building
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ZD1

2zd1


Resolution: 1.51→35.853 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1932 3833 2.02 %RANDOM
Rwork0.1542 ---
all0.155 195940 --
obs0.155 190062 97 %-
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 69.966 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.0783 Å20 Å2-3.2985 Å2
2---2.3632 Å2-0 Å2
3---1.2848 Å2
Refinement stepCycle: LAST / Resolution: 1.51→35.853 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7955 0 79 824 8858
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0138280
X-RAY DIFFRACTIONf_angle_d1.36211254
X-RAY DIFFRACTIONf_dihedral_angle_d14.1623136
X-RAY DIFFRACTIONf_chiral_restr0.081211
X-RAY DIFFRACTIONf_plane_restr0.0081413
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.51-1.52910.35731470.30276600X-RAY DIFFRACTION94
1.5291-1.54920.31841400.27276648X-RAY DIFFRACTION94
1.5492-1.57050.28561450.24626735X-RAY DIFFRACTION95
1.5705-1.59290.25671570.2226728X-RAY DIFFRACTION95
1.5929-1.61670.25811240.20316747X-RAY DIFFRACTION95
1.6167-1.64190.23831160.18996770X-RAY DIFFRACTION95
1.6419-1.66890.25431310.17476727X-RAY DIFFRACTION96
1.6689-1.69760.23241420.15846784X-RAY DIFFRACTION95
1.6976-1.72850.18471460.14226720X-RAY DIFFRACTION95
1.7285-1.76170.18441380.1346762X-RAY DIFFRACTION96
1.7617-1.79770.2121230.12766781X-RAY DIFFRACTION95
1.7977-1.83680.16441350.11896806X-RAY DIFFRACTION96
1.8368-1.87950.16251420.11186751X-RAY DIFFRACTION96
1.8795-1.92650.15881490.10826784X-RAY DIFFRACTION96
1.9265-1.97860.18291190.11086847X-RAY DIFFRACTION96
1.9786-2.03680.15681500.11556904X-RAY DIFFRACTION97
2.0368-2.10260.14541370.11556976X-RAY DIFFRACTION99
2.1026-2.17770.16851580.11867067X-RAY DIFFRACTION99
2.1777-2.26490.17731330.11917117X-RAY DIFFRACTION100
2.2649-2.36790.16591480.12457059X-RAY DIFFRACTION100
2.3679-2.49270.18681450.13157134X-RAY DIFFRACTION100
2.4927-2.64890.20061500.13917093X-RAY DIFFRACTION100
2.6489-2.85330.16451660.14687109X-RAY DIFFRACTION100
2.8533-3.14030.17681510.15147168X-RAY DIFFRACTION100
3.1403-3.59440.18651480.16047136X-RAY DIFFRACTION100
3.5944-4.52710.18721510.15397159X-RAY DIFFRACTION99
4.5271-35.8630.23691420.20057117X-RAY DIFFRACTION97

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