6UJZ

HIV-1 wild-type reverse transcriptase-DNA complex with (+)-FTC-TP

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

Starting Model: experimental
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Ligand Structure Quality Assessment 


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Literature

Elucidating molecular interactions ofL-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance.

Hung, M., Tokarsky, E.J., Lagpacan, L., Zhang, L., Suo, Z., Lansdon, E.B.

(2019) Commun Biol 2: 469-469

  • DOI: https://doi.org/10.1038/s42003-019-0706-x
  • Primary Citation of Related Structures:  
    6UIR, 6UIS, 6UIT, 6UJX, 6UJY, 6UJZ, 6UK0

  • PubMed Abstract: 

    Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/ K d ) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (-)-FTC-TP and (-)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3'-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L -nucleotides and moderately higher (>9-fold) K d for the D -isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.

    • Organizational Affiliation: 

    1Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404 USA.


Macromolecules

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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
p66 Reverse transcriptase/RNaseH572HIV-1 M:B_HXB2RMutation(s): 2 
Gene Names: gag-pol
EC: 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.13 (PDB Primary Data)
UniProt
Find proteins for P04585 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04585 
Go to UniProtKB:  P04585
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04585
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p51 Reverse transcriptase/RNaseH440HIV-1 M:B_HXB2RMutation(s): 1 
Gene Names: gag-pol
EC: 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.13 (PDB Primary Data)
UniProt
Find proteins for P04585 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04585 
Go to UniProtKB:  P04585
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04585
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
primer DNAC [auth P]21Human immunodeficiency virus 1
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 4
MoleculeChains LengthOrganismImage
template DNAD [auth T]27Human immunodeficiency virus 1
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
N8G BindingDB:  6UJZ Ki: 501 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 168.277α = 90
b = 168.829β = 90
c = 102.548γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-25
    Type: Initial release
  • Version 1.1: 2020-01-08
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description