1W3Y

Crystal structure of S. pneumoniae hyaluronate lyase in complex with palmitoyl-vitamin C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

L-Ascorbic Acid 6-Hexadecanoate, a Potent Hyaluronidase Inhibitor: X-Ray Structure and Molecular Modeling of Enzyme-Inhibitor Complexes

Botzki, A.Rigden, D.J.Braun, S.Nukui, M.Salmen, S.Hoechstetter, J.Bernhardt, G.Dove, S.Jedrzejas, M.J.Buschauer, A.

(2004) J Biol Chem 279: 45990

  • DOI: https://doi.org/10.1074/jbc.M406146200
  • Primary Citation of Related Structures:  
    1W3Y

  • PubMed Abstract: 

    Hyaluronidases are enzymes that degrade hyaluronan, an important component of the extracellular matrix. The mammalian hyaluronidases are considered to be involved in many (patho)physiological processes like fertilization, tumor growth, and metastasis. Bacterial hyaluronidases, also termed hyaluronate lyases, contribute to the spreading of microorganisms in tissues. Such roles for hyaluronidases suggest that inhibitors could be useful pharmacological tools. Potent and selective inhibitors are not known to date, although L-ascorbic acid has been reported to be a weak inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL). The x-ray structure of SpnHL complexed with L-ascorbic acid has been elucidated suggesting that additional hydrophobic interactions might increase inhibitory activity. Here we show that L-ascorbic acid 6-hexadecanoate (Vcpal) is a potent inhibitor of both streptococcal and bovine testicular hyaluronidase (BTH). Vcpal showed strong inhibition of Streptococcus agalactiae hyaluronate lyase with an IC(50) of 4 microM and weaker inhibition of SpnHL and BTH with IC(50) values of 100 and 56 microM, respectively. To date, Vcpal has proved to be one of the most potent inhibitors of hyaluronidase. We also determined the x-ray structure of the SpnHL-Vcpal complex and confirmed the hypothesis that additional hydrophobic interactions with Phe-343, His-399, and Thr-400 in the active site led to increased inhibition. A homology structural model of BTH was also generated to suggest binding modes of Vcpal to this hyaluronidase. The long alkyl chain seemed to interact with an extended, hydrophobic channel formed by mostly conserved amino acids Ala-84, Leu-91, Tyr-93, Tyr-220, and Leu-344 in BTH.


  • Organizational Affiliation

    Institute of Pharmacy, University of Regensburg, Universitätsstrasse 31, 93040 Regensburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HYALURONATE LYASE731Streptococcus pneumoniaeMutation(s): 0 
EC: 4.2.2.1
UniProt
Find proteins for Q54873 (Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4))
Explore Q54873 
Go to UniProtKB:  Q54873
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ54873
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PVC
Query on PVC

Download Ideal Coordinates CCD File 
B [auth A](2E,4R,5S)-2,3,4,5-TETRAHYDROXY-6-(PALMITOYLOXY)HEX-2-ENOIC ACID
C22 H40 O8
XWTWKBKNEMLBKW-KCWNHAIFSA-N
XYL
Query on XYL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
Xylitol
C5 H12 O5
HEBKCHPVOIAQTA-SCDXWVJYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
PVC Binding MOAD:  1W3Y IC50: 1.00e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.131α = 90
b = 102.714β = 90
c = 102.41γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-08-26
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Derived calculations, Other, Structure summary