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- PDB-3bgr: Crystal structure of K103N/Y181C mutant HIV-1 reverse transcripta... -

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Basic information

Entry
Database: PDB / ID: 3bgr
TitleCrystal structure of K103N/Y181C mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (Rilpivirine), a non-nucleoside RT inhibitor
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsTRANSFERASE / HYDROLASE / P51/P66 / HETERO DIMER / NNRTI / NONNUCLEOSIDE INHIBITOR / AIDS / HIV / R278474 / RILPIVIRINE / DIARYLPYRIMIDINE / DAPY / DNA RECOMBINATION / RNA-DIRECTED DNA POLYMERASE / DNA POLYMERASE / ENDONUCLEASE / MULTIFUNCTIONAL ENZYME / K103N / Y181C
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-T27 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsDas, K. / Bauman, J.D. / Clark Jr., A.D. / Shatkin, A.J. / Arnold, E.
Citation
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.
#1: 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.
#2: 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.
#3: 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.
#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.
History
DepositionNov 27, 2007Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 12, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 18, 2012Group: Non-polymer description
Revision 1.3Jun 17, 2015Group: Non-polymer description
Revision 1.4Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 1, 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
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,3824
Polymers113,9542
Non-polymers4282
Water8,557475
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.840, 73.180, 108.920
Angle α, β, γ (deg.)90.00, 100.79, 90.00
Int Tables number5
Space group name H-MC121
DetailsP66/P51 HETERODIMER

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Components

#1: Protein Reverse transcriptase/ribonuclease H / REVERSE TRANSCRIPTASE P66 SUBUNIT


Mass: 63914.129 Da / Num. of mol.: 1 / Fragment: P66 / Mutation: K103N, K172A, K173A, Y181C, C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: gag-pol / Plasmid: pRT52A / Production host: Escherichia coli (E. coli) / Strain (production host): BH10 ISOLATE
References: UniProt: P03366, RNA-directed DNA polymerase, DNA-directed DNA polymerase, ribonuclease H
#2: Protein p51 RT / REVERSE TRANSCRIPTASE P51 SUBUNIT


Mass: 50039.488 Da / Num. of mol.: 1 / Fragment: P51 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: gag-pol / Plasmid: pRT52A / Production host: Escherichia coli (E. coli) / Strain (production host): BH10 ISOLATE / References: UniProt: P03366
#3: Chemical ChemComp-T27 / 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile / Rilpivirine


Mass: 366.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N6 / Comment: medication*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 475 / 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: 2.8 Å3/Da / Density % sol: 56.03 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: PEG 8000, AMMONIUM SULFATE, MGCL2, IMIDAZOLE, pH 6.80, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 0.98 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 20, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 73049 / % possible obs: 98.9 % / Observed criterion σ(I): -1 / Redundancy: 3.4 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 11.3
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.568 / Num. unique all: 7044 / % possible all: 96

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1S6Q

1s6q


Resolution: 2.1→40 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 2593226.41 / 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 2189 3 %RANDOM
Rwork0.228 ---
obs0.228 72840 98.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.1468 Å2 / ksol: 0.316242 e/Å3
Displacement parametersBiso mean: 58 Å2
Baniso -1Baniso -2Baniso -3
1--5.36 Å20 Å2-6.57 Å2
2---1.96 Å20 Å2
3---7.32 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.34 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.42 Å0.42 Å
Refinement stepCycle: LAST / Resolution: 2.1→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7908 0 32 475 8415
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.95
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it2.461.5
X-RAY DIFFRACTIONc_mcangle_it3.872
X-RAY DIFFRACTIONc_scbond_it4.52
X-RAY DIFFRACTIONc_scangle_it5.892.5
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.019 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.358 359 3 %
Rwork0.339 11520 -
obs--97.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2278.paramion.top
X-RAY DIFFRACTION3ion.paramwater.top
X-RAY DIFFRACTION4water_rep.param278.top
X-RAY DIFFRACTION5edo.paramedo.top

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