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- PDB-4ncg: Discovery of Doravirine, an orally bioavailable non-nucleoside re... -

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Basic information

Entry
Database: PDB / ID: 4ncg
TitleDiscovery of Doravirine, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses
Components
  • Reverse transcriptase/ribonuclease H
  • p51 RT
KeywordsTransferase/Inhhibitor / Hydrolase/Inhhibitor / HIV-1 reverse transcriptase / non-nucleoside inhibition / Wild type RT Transferase-inhibitor complex / Hydrolase-inhibitor complex / Transferase-Inhhibitor / Hydrolase-Inhhibitor complex
Function / homology
Function and homology information


integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus ...integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Binding and entry of HIV virion / viral life cycle / : / : / Assembly Of The HIV Virion / HIV-1 retropepsin / retroviral ribonuclease H / Budding and maturation of HIV virion / exoribonuclease H / exoribonuclease H activity / protein processing / host multivesicular body / RNA-directed DNA polymerase / viral penetration into host nucleus / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / peptidase 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 / DNA binding / RNA binding / zinc ion binding / membrane / identical protein 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
Chem-2KW / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsYan, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.
Authors: Cote, B. / Burch, J.D. / Asante-Appiah, E. / Bayly, C. / Bedard, L. / Blouin, M. / Campeau, L.C. / Cauchon, E. / Chan, M. / Chefson, A. / Coulombe, N. / Cromlish, W. / Debnath, S. / ...Authors: Cote, B. / Burch, J.D. / Asante-Appiah, E. / Bayly, C. / Bedard, L. / Blouin, M. / Campeau, L.C. / Cauchon, E. / Chan, M. / Chefson, A. / Coulombe, N. / Cromlish, W. / Debnath, S. / Deschenes, D. / Dupont-Gaudet, K. / Falgueyret, J.P. / Forget, R. / Gagne, S. / Gauvreau, D. / Girardin, M. / Guiral, S. / Langlois, E. / Li, C.S. / Nguyen, N. / Papp, R. / Plamondon, S. / Roy, A. / Roy, S. / Seliniotakis, R. / St-Onge, M. / Ouellet, S. / Tawa, P. / Truchon, J.F. / Vacca, J. / Wrona, M. / Yan, Y. / Ducharme, Y.
History
DepositionOct 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2022Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / struct_ref_seq_dif / struct_site
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 / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)117,0523
Polymers116,6272
Non-polymers4261
Water1,54986
1
A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules

A: Reverse transcriptase/ribonuclease H
B: p51 RT
hetero molecules


Theoretical massNumber of molelcules
Total (without water)234,1056
Polymers233,2534
Non-polymers8512
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area16070 Å2
ΔGint-65 kcal/mol
Surface area84800 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5640 Å2
ΔGint-24 kcal/mol
Surface area44800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.385, 153.618, 154.624
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Detailsheterodimer (A and B chain)

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Components

#1: Protein Reverse transcriptase/ribonuclease H


Mass: 64895.316 Da / Num. of mol.: 1 / Fragment: HIV-1 Reverse Transcriptase p66
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: HXB2 ISOLATE
References: UniProt: P04585, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Protein p51 RT


Mass: 51731.418 Da / Num. of mol.: 1 / Fragment: HIV-1 Reverse Transcriptase p51
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: HXB2 ISOLATE
References: UniProt: P04585, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#3: Chemical ChemComp-2KW / 3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile / Doravirine / Doravirine


Mass: 425.749 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11ClF3N5O3 / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 3.01 Å3/Da / Density % sol: 59.19 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.1
Details: sodium citrate, pH 6.1, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 18, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. all: 43282 / Num. obs: 43022 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Biso Wilson estimate: 81.82 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 12.1
Reflection shellResolution: 2.65→2.74 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.592 / Num. unique all: 4270 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
BUSTER2.11.5refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.58→26.01 Å / Cor.coef. Fo:Fc: 0.9444 / Cor.coef. Fo:Fc free: 0.9212 / SU R Cruickshank DPI: 0.474 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2595 2163 5.04 %RANDOM
Rwork0.217 ---
obs0.2191 42941 96.31 %-
Displacement parametersBiso mean: 78.02 Å2
Baniso -1Baniso -2Baniso -3
1-8.1076 Å20 Å20 Å2
2--1.3034 Å20 Å2
3----9.4109 Å2
Refine analyzeLuzzati coordinate error obs: 0.434 Å
Refinement stepCycle: LAST / Resolution: 2.58→26.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7798 0 29 86 7913
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018036HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1410928HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2788SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes216HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1101HARMONIC5
X-RAY DIFFRACTIONt_it8036HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.83
X-RAY DIFFRACTIONt_other_torsion20.38
X-RAY DIFFRACTIONt_chiral_improper_torsion1040SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact8988SEMIHARMONIC4
LS refinement shellResolution: 2.58→2.65 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3848 115 6.09 %
Rwork0.2948 1772 -
all0.3001 1887 -
obs--96.31 %

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