6KDN

HIV-1 reverse transcriptase with Q151M/Y115F/F116Y:DNA:dGTP ternary complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine.

Yasutake, Y.Hattori, S.I.Tamura, N.Matsuda, K.Kohgo, S.Maeda, K.Mitsuya, H.

(2020) Sci Rep 10: 3021-3021

  • DOI: https://doi.org/10.1038/s41598-020-59775-w
  • Primary Citation of Related Structures:  
    6KDJ, 6KDK, 6KDM, 6KDN, 6KDO

  • PubMed Abstract: 

    Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIV Y115F/F116Y/Q151M ) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIV Y115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RT Y115F/F116Y/Q151M :DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RT Y115F/F116Y/Q151M/F160M/M184V :DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.


  • Organizational Affiliation

    Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, 062-8517, Japan. [email protected].


Macromolecules

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 reverse transcriptase p66 subunitA,
D [auth C]
557Human immunodeficiency virus 1Mutation(s): 5 
Gene Names: pol
UniProt
Find proteins for P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5))
Explore P12497 
Go to UniProtKB:  P12497
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12497
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 RT p51 subunitB,
E [auth D]
444Human immunodeficiency virus 1Mutation(s): 2 
UniProt
Find proteins for P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5))
Explore P12497 
Go to UniProtKB:  P12497
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12497
Sequence Annotations
Expand
  • Reference Sequence
Find similar nucleic acids by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains LengthOrganismImage
DNA/RNA (38-MER)C [auth E],
F
38synthetic construct
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DGT (Subject of Investigation/LOI)
Query on DGT

Download Ideal Coordinates CCD File 
H [auth A],
M [auth C]
2'-DEOXYGUANOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O13 P3
HAAZLUGHYHWQIW-KVQBGUIXSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth A],
J [auth B],
K [auth B],
N [auth D],
O [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
G [auth A],
L [auth C]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 284.167α = 90
b = 284.167β = 90
c = 95.521γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Japan Agency for Medical Research and Development (AMED)JapanJP19fk0310113

Revision History  (Full details and data files)

  • Version 1.0: 2020-03-04
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description