5ULT

HIV-1 wild Type protease with GRL-100-13A (a Crown-like Oxotricyclic Core as the P2-Ligand with the sulfonamide isostere as the P2' group)

  • Classification: hydrolase/hydrolase inhibitor
  • Organism(s): Human immunodeficiency virus 1
  • Expression System: Escherichia coli BL21(DE3)
  • Mutation(s): Yes 

  • Deposited: 2017-01-25 Released: 2017-05-03 
  • Deposition Author(s): Wang, Y.-F., Agniswamy, J., Weber, I.T.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), Department of Energy (DOE, United States), National Institutes of Health/National Cancer Institute (NIH/NCI), Ministry of Education, Culture, Sports, Science and Technology (Japan), Ministry of Health, Welfare, and Labor, Purdue University

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.

Ghosh, A.K.Rao, K.V.Nyalapatla, P.R.Osswald, H.L.Martyr, C.D.Aoki, M.Hayashi, H.Agniswamy, J.Wang, Y.F.Bulut, H.Das, D.Weber, I.T.Mitsuya, H.

(2017) J Med Chem 60: 4267-4278

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00172
  • Primary Citation of Related Structures:  
    5ULT

  • PubMed Abstract: 

    Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.


  • Organizational Affiliation

    Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, 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): 5 
Gene Names: pol
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8FM
Query on 8FM

Download Ideal Coordinates CCD File 
E [auth B](3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate
C30 H40 N2 O8 S
JVINLJIUYCLBEU-JBQMQJJESA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8FM Binding MOAD:  5ULT Ki: 0.01 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.175 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.336α = 90
b = 86.776β = 90
c = 45.252γ = 90
Software Package:
Software NamePurpose
PHASERphasing
SHELXL-97refinement
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 StatesGM53386
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM62920
Department of Energy (DOE, United States)United StatesW-31-109-Eng-38
National Institutes of Health/National Cancer Institute (NIH/NCI)United Statesthe Intramural Research Program of the Center for Cancer Research
Ministry of Education, Culture, Sports, Science and Technology (Japan)JapanGrant-in-Aid for Scientific Research (Priority Areas)
Ministry of Health, Welfare, and LaborJapana Grant for Promotion of AIDS Research
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japanhe Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo)
Purdue UniversityUnited StatesPurdue University Center for Cancer Research

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-03
    Type: Initial release
  • Version 1.1: 2017-06-07
    Changes: Data collection, Database references
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence, Refinement description
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description