4EXH

The crystal structure of xmrv protease complexed with acetyl-pepstatin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin.

Matuz, K.Motyan, J.Li, M.Wlodawer, A.

(2012) FEBS J 279: 3276-3286

  • DOI: https://doi.org/10.1111/j.1742-4658.2012.08714.x
  • Primary Citation of Related Structures:  
    4EXH

  • PubMed Abstract: 

    The kinetic properties of two classical inhibitors of aspartic proteases (PRs), pepstatin A and acetyl-pepstatin, were compared in their interactions with HIV-1 and xenotropic murine leukemia virus related virus (XMRV) PRs. Both compounds are substantially weaker inhibitors of XMRV PR than of HIV-1 PR. Previous kinetic and structural studies characterized HIV-1 PR-acetyl-pepstatin and XMRV PR-pepstatin A complexes and suggested dramatically different binding modes. Interaction energies were calculated for the possible binding modes and suggested a strong preference for the one-inhibitor binding mode for HIV-1 PR-acetyl-pepstatin and the two-inhibitor binding mode for XMRV PR-pepstatin A interactions. Comparison of the molecular models suggested that in the case of XMRV PR the relatively unfavorable interactions at S3' and the favorable interactions at S4 and S4' sites with the statine residues may shift the ground state binding towards the two-inhibitor binding mode, whereas the single molecule ground state binding of statines to the HIV-1 PR appear to be more favorable. The preferred single molecular binding to HIV-1 PR allows the formation of the transition state complex, represented by substantially better binding constants. Intriguingly, the crystal structure of the complex of acetyl-pepstatin with XMRV PR has shown a mixed type of binding: the unusual binding mode of two molecules of the inhibitor to the enzyme, in a mode very similar to the previously determined complex with pepstatin A, together with the classical binding mode found for HIV-1 PR. The structure is thus in good agreement with the very similar interaction energies calculated for the two types of binding.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Hungary.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Putative gag-pro-pol polyprotein
A, B
132DG-75 Murine leukemia virusMutation(s): 0 
Gene Names: GAG-POL
UniProt
Find proteins for Q9E7M1 (DG-75 Murine leukemia virus)
Explore Q9E7M1 
Go to UniProtKB:  Q9E7M1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9E7M1
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYL-PEPSTATINC [auth J],
D [auth M],
E [auth P]
6StreptomycesMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMT
Query on FMT

Download Ideal Coordinates CCD File 
F [auth M]FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.314α = 90
b = 65.21β = 90
c = 69.468γ = 90
Software Package:
Software NamePurpose
MAR345data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-01
    Type: Initial release
  • Version 1.1: 2012-11-14
    Changes: Database references
  • Version 1.2: 2012-12-12
    Changes: Other
  • Version 1.3: 2017-11-15
    Changes: Advisory, Refinement description