5XN0

HIV-1 reverse transcriptase Q151M:DNA binary complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

Starting Model: experimental
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This is version 2.1 of the entry. See complete history


Literature

HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir.

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

(2018) Sci Rep 8: 1624-1624

  • DOI: https://doi.org/10.1038/s41598-018-19602-9
  • Primary Citation of Related Structures:  
    5XN0, 5XN1, 5XN2

  • PubMed Abstract: 

    Hepatitis B virus (HBV) reverse transcriptase (RT) is essential for viral replication and is an important drug target. Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RT Q151M :DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3'-end nucleotide, compared to the position of bound dGTP and previously reported NRTI/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV/HIV-1 RT inhibitors to overcome critical drug resistance.


  • Organizational Affiliation

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


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pol proteinA,
D [auth C]
557Human immunodeficiency virus 1Mutation(s): 3 
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
Pol proteinB,
E [auth D]
444Human immunodeficiency virus 1Mutation(s): 2 
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
Expand
  • Reference Sequence
Find similar nucleic acids by: 3D Structure
Entity ID: 3
MoleculeChains LengthOrganismImage
38-MER DNA aptamerC [auth E],
F
38synthetic construct
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose
G
2N/A
Glycosylation Resources
GlyTouCan:  G05551OP
GlyCosmos:  G05551OP
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 284.091α = 90
b = 284.091β = 90
c = 95.605γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata processing
MOLREPphasing
Cootmodel building

Structure Validation

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Entry History & Funding Information

Deposition Data


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

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description, Structure summary