5CON

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-015


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir.

Aoki, M.Hayashi, H.Yedidi, R.S.Martyr, C.D.Takamatsu, Y.Aoki-Ogata, H.Nakamura, T.Nakata, H.Das, D.Yamagata, Y.Ghosh, A.K.Mitsuya, H.

(2015) J Virol 90: 2180-2194

  • DOI: https://doi.org/10.1128/JVI.01829-15
  • Primary Citation of Related Structures:  
    5COK, 5CON, 5COO, 5COP

  • PubMed Abstract: 

    We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1(WT)), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV(R) P51); the three compounds remained active against HIV-1DRV(R) P51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR.


  • Organizational Affiliation

    Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 protease
A, B
99Human immunodeficiency virus 1Mutation(s): 1 
Gene Names: pol
UniProt
Find proteins for G0X8E8 (Human immunodeficiency virus 1)
Explore G0X8E8 
Go to UniProtKB:  G0X8E8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupG0X8E8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
52W
Query on 52W

Download Ideal Coordinates CCD File 
C [auth B](3R,3aS,4S,7aS)-3-hydroxyhexahydro-4H-furo[2,3-b]pyran-4-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate
C29 H40 N2 O9 S
BCSIHXKFONPDJO-QWGZUQTQSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.786α = 90
b = 62.786β = 90
c = 81.907γ = 120
Software Package:
Software NamePurpose
SCALEPACKdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-13
    Type: Initial release
  • Version 1.1: 2016-02-24
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence, Data collection, Database references, Derived calculations
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references