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

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Entry
Database: PDB / ID: 2iaj
TitleCrystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with ATP
Components(Reverse transcriptase/ribonuclease ...) x 2
KeywordsTRANSFERASE / RT / NNRTI / NONNUCLEOSIDE INHIBITOR / DRUG RESISTANCE / DNA POLYMERIZATION / 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 / 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 / viral penetration into host nucleus / host multivesicular body / 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 / 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 / Alpha-Beta Plaits / Roll / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / : / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 BH10
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 8, 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: Non-polymer description / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / 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.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_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)117,2769
Polymers116,3962
Non-polymers8797
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6950 Å2
ΔGint-53 kcal/mol
Surface area45510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)237.400, 71.130, 94.210
Angle α, β, γ (deg.)90.00, 105.86, 90.00
Int Tables number5
Space group name H-MC121
Detailsp66/p51 hetero dimer

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Components

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

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


Mass: 64425.855 Da / Num. of mol.: 1 / Fragment: p66 / Mutation: K103N, Y181C, 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: K103N, Y181C, 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

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Non-polymers , 5 types, 315 molecules

#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 3.35 Å3/Da / Density % sol: 63.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: PEG 8000, Bis_Tris propane, ammonium sulfate, glycerol, MnCL2, ATP, VAPOR DIFFUSION, HANGING DROP, temperature 277K, pH 6.8

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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: 2.5→40 Å / Num. obs: 48538 / % possible obs: 92.2 % / Observed criterion σ(I): -1 / Rmerge(I) obs: 0.057 / Χ2: 0.92 / Net I/σ(I): 15.2
Reflection shellResolution: 2.5→2.54 Å / Rmerge(I) obs: 0.367 / Num. unique all: 1809 / Χ2: 1.219 / % possible all: 68.5

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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: 1DLO

1dlo


Resolution: 2.5→19.96 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 789848.625 / 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
Rfree0.284 1817 4 %RANDOM
Rwork0.233 ---
obs-45021 85.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.368 Å2 / ksol: 0.283 e/Å3
Displacement parametersBiso mean: 72.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.15 Å20 Å218.59 Å2
2---4.88 Å20 Å2
3---5.03 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.52 Å0.41 Å
Luzzati d res low-5 Å
Luzzati sigma a0.93 Å0.79 Å
Refinement stepCycle: LAST / Resolution: 2.5→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7822 0 47 308 8177
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.011
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d23.8
X-RAY DIFFRACTIONc_improper_angle_d1.1
X-RAY DIFFRACTIONc_mcbond_it2.361.5
X-RAY DIFFRACTIONc_mcangle_it3.952
X-RAY DIFFRACTIONc_scbond_it3.582
X-RAY DIFFRACTIONc_scangle_it5.262.5
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.035 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.485 192 3.7 %
Rwork0.456 4953 -
obs-5145 59.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramatp.top
X-RAY DIFFRACTION4atp.parion.top
X-RAY DIFFRACTION5gol.pargol.top

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