5C42

Crystal Structure of HIV-1 Reverse Transcriptase (K101P) Variant in Complex with 8-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)indolizine-2-carbonitrile (JLJ555), a non-nucleoside inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.244 
  • R-Value Observed: 0.247 

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This is version 1.4 of the entry. See complete history. 


Literature

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.

Gray, W.T., Frey, K.M., Laskey, S.B., Mislak, A.C., Spasov, K.A., Lee, W.G., Bollini, M., Siliciano, R.F., Jorgensen, W.L., Anderson, K.S.

(2015) ACS Med Chem Lett 6: 1075-1079

  • DOI: https://doi.org/10.1021/acsmedchemlett.5b00254
  • Primary Citation of Related Structures:  
    5C42

  • PubMed Abstract: 

    Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.

    • Organizational Affiliation: 

    Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Reverse Transcriptase, p66 subunit557Human immunodeficiency virus type 1 BH10Mutation(s): 4 
Gene Names: gag-pol
EC: 3.4.23.16 (PDB Primary Data), 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.13 (PDB Primary Data), 3.1.13.2 (PDB Primary Data)
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
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 Reverse Transcriptase, p51 subunit428Human immunodeficiency virus type 1 BH10Mutation(s): 1 
Gene Names: gag-pol
EC: 3.4.23.16 (PDB Primary Data), 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.13 (PDB Primary Data), 3.1.13.2 (PDB Primary Data)
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
29T
Query on 29T
Download Ideal Coordinates CCD File 
C [auth A]8-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}indolizine-2-carbonitrile
C21 H16 N4 O4
UUVBMMWJHPNLHN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
29T BindingDB:  5C42 IC50: 1.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.244 
  • R-Value Observed: 0.247 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 224.198α = 90
b = 69.008β = 106.49
c = 104.283γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000phasing
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI44616
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM49551
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI104334

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-11
    Type: Initial release
  • Version 1.1: 2017-09-13
    Changes: Author supporting evidence, Derived calculations
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references