6CVY

Crystal structure of HCV NS3/4A WT protease in complex with AJ-21 (MK-5172 linear analogue)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.147 
  • R-Value Observed: 0.148 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.

Rusere, L.N.Matthew, A.N.Lockbaum, G.J.Jahangir, M.Newton, A.Petropoulos, C.J.Huang, W.Kurt Yilmaz, N.Schiffer, C.A.Ali, A.

(2018) ACS Med Chem Lett 9: 691-696

  • DOI: https://doi.org/10.1021/acsmedchemlett.8b00150
  • Primary Citation of Related Structures:  
    6CVW, 6CVX, 6CVY

  • PubMed Abstract: 

    A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NS3 protease201Hepacivirus hominisMutation(s): 0 
UniProt
Find proteins for A0A0B4WYC6 (Hepacivirus hominis)
Explore A0A0B4WYC6 
Go to UniProtKB:  A0A0B4WYC6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A0B4WYC6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FHD (Subject of Investigation/LOI)
Query on FHD

Download Ideal Coordinates CCD File 
F [auth A]3-methyl-N-[(pentyloxy)carbonyl]-L-valyl-(4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-L-prolinamide
C36 H49 Cl N6 O9 S
GCSLYGDUYMRXAE-BTMIYQIWSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FHD Binding MOAD:  6CVY Ki: 3.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.147 
  • R-Value Observed: 0.148 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.453α = 90
b = 58.483β = 90
c = 59.729γ = 90
Software Package:
Software NamePurpose
HKL-3000data scaling
PHASERphasing
PHENIXrefinement
Cootmodel building

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 Allergy and Infectious Diseases (NIH/NIAID)United StatesR01 AI085051
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesF31 GM119345

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-08
    Type: Initial release
  • Version 1.1: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description