4FIV

FIV PROTEASE COMPLEXED WITH AN INHIBITOR LP-130


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Work: 0.149 

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This is version 1.3 of the entry. See complete history


Literature

Toward a universal inhibitor of retroviral proteases: comparative analysis of the interactions of LP-130 complexed with proteases from HIV-1, FIV, and EIAV.

Kervinen, J.Lubkowski, J.Zdanov, A.Bhatt, D.Dunn, B.M.Hui, K.Y.Powell, D.J.Kay, J.Wlodawer, A.Gustchina, A.

(1998) Protein Sci 7: 2314-2323

  • DOI: https://doi.org/10.1002/pro.5560071108
  • Primary Citation of Related Structures:  
    1ODY, 2FMB, 4FIV

  • PubMed Abstract: 

    One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3' positions, which might be responsible for the variation in the Ki values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds.


  • Organizational Affiliation

    Macromolecular Structure Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FELINE IMMUNODEFICIENCY VIRUS PROTEASE113Feline immunodeficiency virusMutation(s): 0 
EC: 3.4.23.16
UniProt
Find proteins for Q66972 (Feline immunodeficiency virus)
Explore Q66972 
Go to UniProtKB:  Q66972
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ66972
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LP1
Query on LP1

Download Ideal Coordinates CCD File 
B [auth A]4-[2-(2-ACETYLAMINO-3-NAPHTALEN-1-YL-PROPIONYLAMINO)-4-METHYL-PENTANOYLAMINO]-3-HYDROXY-6-METHYL-HEPTANOIC ACID [1-(1-CARBAMOYL-2-NAPHTHALEN-1-YL-ETHYLCARBAMOYL)-PROPYL]-AMIDE
C45 H58 N6 O7
ACPDNLLISIAERE-ZYWZKTPASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LP1 Binding MOAD:  4FIV Ki: 300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Work: 0.149 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.65α = 90
b = 50.65β = 90
c = 74.5γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
PROFFTrefinement
X-PLORrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1999-01-13
    Type: Initial release
  • Version 1.1: 2008-03-25
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2023-08-09
    Changes: Database references, Derived calculations, Other, Refinement description