4YGF

Crystal structure of the complex of Helicobacter pylori alpha-Carbonic Anhydrase with acetazolamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis for the Inhibition of Helicobacter pylori alpha-Carbonic Anhydrase by Sulfonamides.

Modakh, J.K.Liu, Y.C.Machuca, M.A.Supuran, C.T.Roujeinikova, A.

(2015) PLoS One 10: e0127149-e0127149

  • DOI: https://doi.org/10.1371/journal.pone.0127149
  • Primary Citation of Related Structures:  
    4YGF, 4YHA

  • PubMed Abstract: 

    Periplasmic α-carbonic anhydrase of Helicobacter pylori (HpαCA), an oncogenic bacterium in the human stomach, is essential for its acclimation to low pH. It catalyses the conversion of carbon dioxide to bicarbonate using Zn(II) as the cofactor. In H. pylori, Neisseria spp., Brucella suis and Streptococcus pneumoniae this enzyme is the target for sulfonamide antibacterial agents. We present structural analysis correlated with inhibition data, on the complexes of HpαCA with two pharmacological inhibitors of human carbonic anhydrases, acetazolamide and methazolamide. This analysis reveals that two sulfonamide oxygen atoms of the inhibitors are positioned proximal to the putative location of the oxygens of the CO2 substrate in the Michaelis complex, whilst the zinc-coordinating sulfonamide nitrogen occupies the position of the catalytic water molecule. The structures are consistent with acetazolamide acting as site-directed, nanomolar inhibitors of the enzyme by mimicking its reaction transition state. Additionally, inhibitor binding provides insights into the channel for substrate entry and product exit. This analysis has implications for the structure-based design of inhibitors of bacterial carbonic anhydrases.


  • Organizational Affiliation

    Department of Microbiology, Faculty of Biomedical and Psychological Sciences, Monash University, Clayton, Victoria, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Alpha-carbonic anhydrase
A, B, C, D, E
A, B, C, D, E, F, G, H
234Helicobacter pylori 26695Mutation(s): 0 
Gene Names: C694_06140
UniProt
Find proteins for A0A0M3KL20 (Helicobacter pylori (strain ATCC 700392 / 26695))
Explore A0A0M3KL20 
Go to UniProtKB:  A0A0M3KL20
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A0M3KL20
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AZM
Query on AZM

Download Ideal Coordinates CCD File 
CA [auth F]
FA [auth G]
JA [auth H]
K [auth A]
O [auth B]
CA [auth F],
FA [auth G],
JA [auth H],
K [auth A],
O [auth B],
R [auth C],
V [auth D],
Y [auth E]
5-ACETAMIDO-1,3,4-THIADIAZOLE-2-SULFONAMIDE
C4 H6 N4 O3 S2
BZKPWHYZMXOIDC-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
GA [auth G],
KA [auth H],
L [auth A],
S [auth C],
Z [auth E]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
AA [auth F]
DA [auth G]
HA [auth H]
I [auth A]
M [auth B]
AA [auth F],
DA [auth G],
HA [auth H],
I [auth A],
M [auth B],
P [auth C],
T [auth D],
W [auth E]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
BA [auth F]
EA [auth G]
IA [auth H]
J [auth A]
N [auth B]
BA [auth F],
EA [auth G],
IA [auth H],
J [auth A],
N [auth B],
Q [auth C],
U [auth D],
X [auth E]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
CL BindingDB:  4YGF Ki: 2.70e+6 (nM) from 1 assay(s)
AZM Binding MOAD:  4YGF Ki: 21 (nM) from 1 assay(s)
BindingDB:  4YGF Ki: 21 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.78α = 90
b = 133.61β = 90.16
c = 166.54γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction
Cootmodel building
iMOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release
  • Version 1.1: 2015-11-25
    Changes: Data collection
  • Version 1.2: 2015-12-16
    Changes: Structure summary
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description