2OCG

Crystal structure of human valacyclovir hydrolase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Molecular basis of prodrug activation by human valacyclovirase, an alpha-amino acid ester hydrolase.

Lai, L.Xu, Z.Zhou, J.Lee, K.D.Amidon, G.L.

(2008) J Biol Chem 283: 9318-9327

  • DOI: https://doi.org/10.1074/jbc.M709530200
  • Primary Citation of Related Structures:  
    2OCG, 2OCI, 2OCK, 2OCL

  • PubMed Abstract: 

    Chemical modification to improve biopharmaceutical properties, especially oral absorption and bioavailability, is a common strategy employed by pharmaceutical chemists. The approach often employs a simple structural modification and utilizes ubiquitous endogenous esterases as activation enzymes, although such enzymes are often unidentified. This report describes the crystal structure and specificity of a novel activating enzyme for valacyclovir and valganciclovir. Our structural insights show that human valacyclovirase has a unique binding mode and specificity for amino acid esters. Biochemical data demonstrate that the enzyme hydrolyzes esters of alpha-amino acids exclusively and displays a broad specificity spectrum for the aminoacyl moiety similar to tricorn-interacting aminopeptidase F1. Crystal structures of the enzyme, two mechanistic mutants, and a complex with a product analogue, when combined with biochemical analysis, reveal the key determinants for substrate recognition; that is, a flexible and mostly hydrophobic acyl pocket, a localized negative electrostatic potential, a large open leaving group-accommodating groove, and a pivotal acidic residue, Asp-123, after the nucleophile Ser-122. This is the first time that a residue immediately after the nucleophile has been found to have its side chain directed into the substrate binding pocket and play an essential role in substrate discrimination in serine hydrolases. These results as well as a phylogenetic analysis establish that the enzyme functions as a specific alpha-amino acid ester hydrolase. Valacyclovirase is a valuable target for amino acid ester prodrug-based oral drug delivery enhancement strategies.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences and Center for Molecular Drug Targeting, University of Michigan, Ann Arbor, MI 48109-1065, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Valacyclovir hydrolase254Homo sapiensMutation(s): 0 
Gene Names: BPHL
EC: 3.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q86WA6 (Homo sapiens)
Explore Q86WA6 
Go to UniProtKB:  Q86WA6
PHAROS:  Q86WA6
GTEx:  ENSG00000137274 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86WA6
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.182 
  • Space Group: P 62
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.97α = 90
b = 88.97β = 90
c = 86.34γ = 120
Software Package:
Software NamePurpose
d*TREKdata processing
CNSrefinement
PDB_EXTRACTdata extraction
d*TREKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-02-05
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2023-12-27
    Changes: Data collection, Database references, Derived calculations