6OGT

X-ray crystal structure of darunavir-resistant HIV-1 protease (P51) in complex with GRL-001


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.21 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity.

Bulut, H.Hattori, S.I.Aoki-Ogata, H.Hayashi, H.Das, D.Aoki, M.Davis, D.A.Rao, K.V.Nyalapatla, P.R.Ghosh, A.K.Mitsuya, H.

(2020) Sci Rep 10: 10664-10664

  • DOI: https://doi.org/10.1038/s41598-020-65993-z
  • Primary Citation of Related Structures:  
    6OGL, 6OGP, 6OGQ, 6OGS, 6OGT, 6OYD, 6OYR

  • PubMed Abstract: 

    HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2'-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR WT ) and highly-multi-PI-resistance-associated PR DRV R P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2'-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier.


  • Organizational Affiliation

    HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease99Human immunodeficiency virus 1Mutation(s): 0 
Gene Names: pol
UniProt
Find proteins for O38893 (Human immunodeficiency virus 1)
Explore O38893 
Go to UniProtKB:  O38893
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO38893
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JDY (Subject of Investigation/LOI)
Query on JDY

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]-1-(3-fluorophenyl)-3-hydroxybutan-2-yl]carbamate
C33 H41 F N4 O7 S2
JQZKWUOMGKUWLH-LZEUUTFHSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
JDY Binding MOAD:  6OGT IC50: 31 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.21 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.071α = 90
b = 63.071β = 90
c = 82.196γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
xia2data reduction
xia2data scaling
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 Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2020-04-08
    Type: Initial release
  • Version 1.1: 2020-08-26
    Changes: Database references
  • Version 1.2: 2021-04-28
    Changes: Data collection
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description