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- PDB-2i5j: Crystal structure of HIV-1 reverse transcriptase (RT) in complex ... -

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Entry
Database: PDB / ID: 2i5j
TitleCrystal structure of HIV-1 reverse transcriptase (RT) in complex with DHBNH, an RNASE H inhibitor
Components(Reverse transcriptase/ribonuclease H ...) x 2
KeywordsTRANSFERASE / AIDS / HIV / REVERSE TRANSCRIPTASE / RT / RNase H Inhibitor / RNHI / STRUCTURE-BASED DRUG DESIGN / PROTEIN-INHIBITOR COMPLEX / DRUG RESISTANCE
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 / endonuclease activity / 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 / metal ion binding
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
sucrose / alpha-D-glucopyranose / Chem-K05 / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsHimmel, D.M. / Sarafianos, S.G. / Knight, J.L. / Levy, R.M. / Arnold, E.
Citation
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, A.D. / Knight, J.L. / Julias, J.G. / Clark, P.K. / Krogh-Jespersen, K. / Levy, R.M. ...Authors: Himmel, D.M. / Sarafianos, S.G. / Dharmasena, S. / Hossain, M.M. / McCoy-Simandle, K. / Ilina, T. / Clark, 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.
#1: Journal: J.Med.Chem. / Year: 2005
Title: Crystal Structures for HIV-1 Reverse Transcriptase in Complexes with Three Pyridinone Derivatives: A New Class of Non-nucleoside Inhibitors Effective Against a Broad Range of Drug-Resistant Strains
Authors: Himmel, D.M. / Das, K. / Clark Jr., A.D. / Hughes, S.H. / Benjahad, A. / Oumouch, S. / Guillemont, J. / Coupa, S. / Poncelet, A. / Csoka, I. / Meyer, C. / Andries, K. / Nguyen, C.H. / Grierson, D.S. / Arnold, E.
#2: Journal: EMBO J. / Year: 2001
Title: Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA
Authors: Sarafianos, S.G. / Das, K. / Tantillo, C. / Clark Jr., A.D. / Ding, J. / Whitcomb, J.M. / Boyer, P.L. / Hughes, S.H. / Arnold, E.
#3: 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 Jr., A.D. / Lewi, P.J. / Heeres, J. / De Jonge, M.R. / Koymans, L.M.H. / Vinkers, H.M. / Daeyaert, F. / Ludovici, D.W. / Kukla, M.J. / De Corte, B. / Kavash, R.W. / Ho, C.Y. ...Authors: Das, K. / Clark Jr., A.D. / Lewi, P.J. / Heeres, J. / De Jonge, M.R. / Koymans, L.M.H. / 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.J. / Arnold, E.
#4: Journal: J.Mol.Biol. / Year: 1998
Title: Structure and Functional Implications of the Polymerase Active Site Region in a Complex of HIV-1 RT with a Double-Stranded DNA Template-Primer and an Antibody Fab Fragment at 2.8 A Resolution.
Authors: Ding, J. / Das, K. / Hsiou, Y. / Sarafianos, S.G. / Clark Jr., A.D. / Jacobo-Molina, A. / Tantillo, C. / Hughes, S.H. / Arnold, E.
#5: Journal: Structure / Year: 1996
Title: Structure of unliganded HIV-1 reverse transcriptase t 2.7 A resolution: implications of conformational hanges for polymerization and inhibition mechanisms
Authors: Hsiou, Y. / Ding, J. / Das, K. / Clark Jr., A.D. / Hughes, S.H. / Arnold, E.
History
DepositionAug 24, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 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: Refinement description / Category: software
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _struct_asym.entity_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 20, 2021Group: Database references / Structure summary / Category: chem_comp / database_2 / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 2.2Aug 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

Downloads & links

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Assembly

Deposited unit
A: Reverse transcriptase/ribonuclease H P66 subunit
B: Reverse transcriptase/ribonuclease H P51 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,3989
Polymers113,8132
Non-polymers1,5867
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7060 Å2
ΔGint-22 kcal/mol
Surface area48120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.815, 68.896, 104.662
Angle α, β, γ (deg.)90.00, 106.48, 90.00
Int Tables number5
Space group name H-MC121

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Components

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

#1: Protein Reverse transcriptase/ribonuclease H P66 subunit


Mass: 63659.906 Da / Num. of mol.: 1 / Fragment: residues 599-1150 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Strain: ISOLATE BH10 / Gene: gag / Production host: Escherichia coli (E. coli) / References: UniProt: P03366, RNA-directed DNA polymerase
#2: Protein Reverse transcriptase/ribonuclease H P51 subunit


Mass: 50152.648 Da / Num. of mol.: 1 / Fragment: residues 599-1027 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Strain: ISOLATE BH10 / Gene: gag / Production host: Escherichia coli (E. coli)
References: UniProt: P03366, UniProt: Q8UM83*PLUS, RNA-directed DNA polymerase

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Sugars , 2 types, 5 molecules

#3: Polysaccharide beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose / sucrose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: oligosaccharide with reducing-end-to-reducing-end glycosidic bond
References: sucrose
DescriptorTypeProgram
DFrufb2-1DGlcpaGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[ha122h-2b_2-5][a2122h-1a_1-5]/1-2/a2-b1WURCSPDB2Glycan 1.1.0
[][b-D-Fruf]{[(2+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#4: Sugar ChemComp-GLC / alpha-D-glucopyranose / alpha-D-glucose / D-glucose / glucose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C6H12O6
IdentifierTypeProgram
DGlcpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-glucopyranoseCOMMON NAMEGMML 1.0
a-D-GlcpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 38 molecules

#5: Chemical ChemComp-K05 / (E)-3,4-DIHYDROXY-N'-[(2-METHOXYNAPHTHALEN-1-YL)METHYLENE]BENZOHYDRAZIDE


Mass: 336.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N2O4
#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


Mass: 18.015 Da / Num. of mol.: 36 / 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: 3.41 Å3/Da / Density % sol: 63.95 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 50 mM Imidazole pH 6.4, 100 mM Ammonium Sulfate, 15 mM Magnesium Sulfate, 0.6 mM DHBNH, 4% Glucose, 10.5% PEG 8000, 2 mM NaN3, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 4, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 3.15→26 Å / Num. all: 27482 / Num. obs: 24789 / % possible obs: 90.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -1 / Redundancy: 5.2 % / Biso Wilson estimate: 66.849 Å2 / Rsym value: 0.101 / Χ2: 1.001 / Net I/σ(I): 11.1
Reflection shellResolution: 3.15→3.26 Å / Redundancy: 2.8 % / Num. unique all: 2011 / Rsym value: 0.805 / Χ2: 0.847 / % possible all: 74.4

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Phasing

Phasing MRRfactor: 0.365 / R rigid body: 0.351 / Cor.coef. Fo:Fc: 0.759 / Cor.coef. Io to Ic: 0.683
Highest resolutionLowest resolution
Translation4 Å23 Å
Phasing dm shellResolution: 3→25 Å / Delta phi final: 0.123 / FOM : 0.125 / Reflection: 25136

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
PDB_EXTRACT2data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2BE2

2be2


Resolution: 3.15→25.71 Å / Rfactor Rfree error: 0.01 / FOM work R set: 0.819 / Data cutoff high absF: 197616.641 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.269 670 2.8 %RANDOM
Rwork0.234 ---
obs0.2346 23575 87.7 %-
all-26888 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.394 Å2 / ksol: 0.277 e/Å3
Displacement parametersBiso mean: 92.2 Å2
Baniso -1Baniso -2Baniso -3
1-9.92 Å20 Å213.75 Å2
2---7.69 Å20 Å2
3----2.23 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.48 Å0.44 Å
Luzzati d res low-5 Å
Luzzati sigma a0.82 Å0.83 Å
Refinement stepCycle: LAST / Resolution: 3.15→25.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7964 0 108 36 8108
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.9
X-RAY DIFFRACTIONc_dihedral_angle_d23.6
X-RAY DIFFRACTIONc_improper_angle_d1.34
X-RAY DIFFRACTIONc_mcbond_it8.71.5
X-RAY DIFFRACTIONc_mcangle_it12.872
X-RAY DIFFRACTIONc_scbond_it12.42
X-RAY DIFFRACTIONc_scangle_it16.342.5
LS refinement shellResolution: 3.15→3.35 Å / Rfactor Rfree error: 0.049 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.427 77 2.7 %
Rwork0.403 2800 -
obs-2877 64.9 %
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 DIFFRACTION4carbohydrate.paramcarbohydrate.top
X-RAY DIFFRACTION5allprosth.paramallprosth.top

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