6OYR

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-002


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.54 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report

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This is version 1.4 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 P12497 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5))
Explore P12497 
Go to UniProtKB:  P12497
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12497
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NJY (Subject of Investigation/LOI)
Query on NJY

Download Ideal Coordinates CCD File 
B [auth A](3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl {(2S,3R)-1-(3-fluorophenyl)-3-hydroxy-4-[(2-methylpropyl)({2-[(propan-2-yl)amino]-1,3-benzoxazol-6-yl}sulfonyl)amino]butan-2-yl}carbamate
C33 H43 F N4 O8 S
UIWBPCUOFHHOHB-BLFKHSGCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
NJY Binding MOAD:  6OYR IC50: 0.29 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.54 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.82α = 90
b = 62.82β = 90
c = 82.354γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
xia2data scaling
MOLREPphasing

Structure Validation

View Full Validation Report

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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: 2020-05-20
    Type: Initial release
  • Version 1.1: 2020-08-26
    Changes: Database references
  • Version 1.2: 2021-04-28
    Changes: Data collection
  • Version 1.3: 2021-06-09
    Changes: Derived calculations
  • Version 1.4: 2023-10-11
    Changes: Data collection, Database references, Refinement description