1D4L

HIV-1 PROTEASE COMPLEXED WITH A MACROCYCLIC PEPTIDOMIMETIC INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

Tyndall, J.D.Reid, R.C.Tyssen, D.P.Jardine, D.K.Todd, B.Passmore, M.March, D.R.Pattenden, L.K.Bergman, D.A.Alewood, D.Hu, S.H.Alewood, P.F.Birch, C.J.Martin, J.L.Fairlie, D.P.

(2000) J Med Chem 43: 3495-3504

  • DOI: https://doi.org/10.1021/jm000013n
  • Primary Citation of Related Structures:  
    1D4K, 1D4L

  • PubMed Abstract: 

    Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.


  • Organizational Affiliation

    Centre for Drug Design and Development, The University of Queensland, Brisbane, Queensland 4072, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 PROTEASE
A, B
99N/AMutation(s): 4 
EC: 3.4.23.16
UniProt
Find proteins for P03369 (Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2))
Explore P03369 
Go to UniProtKB:  P03369
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03369
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PI9
Query on PI9

Download Ideal Coordinates CCD File 
E [auth A](10S,13S,1'R)-13-[1'-HYDROXY-2'-(N-P-AMINOBENZENESULFONYL-1''-AMINO-3''-METHYLBUTYL)ETHYL]-8,11-DIOXO-10-ISOPROPYL-2-OXA-9,12-DIAZABICYCLO [13.2.2]NONADECA-15,17,18-TRIENE
C32 H48 N4 O6 S
FBNSKSOTNMECSA-FLBADVGZSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
F [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ABA
Query on ABA
A, B
L-PEPTIDE LINKINGC4 H9 N O2ALA
Binding Affinity Annotations 
IDSourceBinding Affinity
PI9 BindingDB:  1D4L Ki: 1.7 (nM) from 1 assay(s)
IC50: min: 45, max: 500 (nM) from 4 assay(s)
PDBBind:  1D4L Ki: 1.7 (nM) from 1 assay(s)
Binding MOAD:  1D4L Ki: 1.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.44α = 90
b = 58.77β = 90
c = 61.71γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2000-10-11
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Refinement description
  • Version 1.4: 2021-11-03
    Changes: Database references, Derived calculations