5TYR

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-121


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency.

Aoki, M.Hayashi, H.Rao, K.V.Das, D.Higashi-Kuwata, N.Bulut, H.Aoki-Ogata, H.Takamatsu, Y.Yedidi, R.S.Davis, D.A.Hattori, S.I.Nishida, N.Hasegawa, K.Takamune, N.Nyalapatla, P.R.Osswald, H.L.Jono, H.Saito, H.Yarchoan, R.Misumi, S.Ghosh, A.K.Mitsuya, H.

(2017) Elife 6

  • DOI: https://doi.org/10.7554/eLife.28020
  • Primary Citation of Related Structures:  
    5TYR, 5TYS

  • PubMed Abstract: 

    Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced HIV-1 transmission at very high rates. However, certain individuals who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due to adverse effects and the emergence of drug-resistant HIV-1 variants. Here, we report GRL-142, a novel HIV-1 protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which has extremely potent activity against all HIV-1 strains examined with IC 50 values of attomolar-to-picomolar concentrations, virtually no effects on cellular growth, extremely high genetic barrier against the emergence of drug-resistant variants, and favorable intracellular and central nervous system penetration. GRL-142 forms optimum polar, van der Waals, and halogen bond interactions with HIV-1 protease and strongly blocks protease dimerization, demonstrating that combined multiple optimizing elements significantly enhance molecular and atomic interactions with a target protein and generate unprecedentedly potent and practically favorable agents.


  • Organizational Affiliation

    Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 0 
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
7O7
Query on 7O7

Download Ideal Coordinates CCD File 
C [auth A](3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl {(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl}carbamate
C33 H42 N4 O7 S2
VXTSDGOABSRKIR-BLFKHSGCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7O7 Binding MOAD:  5TYR IC50: 0.26 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.566α = 90
b = 62.566β = 90
c = 82.666γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
MOLREPphasing
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



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--
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-18
    Type: Initial release
  • Version 1.1: 2017-11-01
    Changes: Database references
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description