4G0C

Neutron structure of acetazolamide-bound human carbonic anhydrase II reveal molecular details of drug binding.


Experimental Data Snapshot

  • Method: NEUTRON DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.267 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding.

Fisher, S.Z.Aggarwal, M.Kovalevsky, A.Y.Silverman, D.N.McKenna, R.

(2012) J Am Chem Soc 134: 14726-14729

  • DOI: https://doi.org/10.1021/ja3068098
  • Primary Citation of Related Structures:  
    4G0C

  • PubMed Abstract: 

    Carbonic anhydrases (CAs) catalyze the hydration of CO(2) forming HCO(3)(-) and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM or the hydrogen atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end, the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target.


  • Organizational Affiliation

    Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2257Homo sapiensMutation(s): 0 
Gene Names: CA2
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AZM
Query on AZM

Download Ideal Coordinates CCD File 
C [auth A]5-ACETAMIDO-1,3,4-THIADIAZOLE-2-SULFONAMIDE
C4 H6 N4 O3 S2
BZKPWHYZMXOIDC-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AZM BindingDB:  4G0C Ki: min: 0.01, max: 104 (nM) from 25 assay(s)
Kd: min: 0.06, max: 46 (nM) from 12 assay(s)
IC50: min: 0.49, max: 4500 (nM) from 61 assay(s)
PDBBind:  4G0C Ki: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: NEUTRON DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.267 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.84α = 90
b = 41.76β = 104.31
c = 72.94γ = 90
Software Package:
Software NamePurpose
PCSdata collection
nCNSrefinement
d*TREKdata reduction
SCALAdata scaling
nCNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-19
    Type: Initial release
  • Version 1.1: 2012-11-21
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description, Structure summary
  • Version 1.3: 2018-04-25
    Changes: Data collection
  • Version 1.4: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description