2X7T

Structures of human carbonic anhydrase II inhibitor complexes reveal a second binding site for steroidal and non-steroidal inhibitors.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Structures of Human Carbonic Anhydrase II/Inhibitor Complexes Reveal a Second Binding Site for Steroidal and Non-Steroidal Inhibitors.

Cozier, G.E.Leese, M.P.Lloyd, M.D.Baker, M.D.Thiyagarajan, N.Acharya, K.R.Potter, B.V.L.

(2010) Biochemistry 49: 3464

  • DOI: https://doi.org/10.1021/bi902178w
  • Primary Citation of Related Structures:  
    2X7S, 2X7T, 2X7U

  • PubMed Abstract: 

    Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon dioxide to hydrogen carbonate, and its role in maintaining pH balance has made it an attractive drug target. Steroidal sulfamate esters, inhibitors of the cancer drug target steroid sulfatase (STS), are sequestered in vivo by CA II in red blood cells, which may be the origin of their excellent drug properties. Understanding the structural basis of this is important for drug design. Structures of CA II complexed with 2-methoxyestradiol 3-O-sulfamate (3), 2-ethylestradiol 3,17-O,O-bis(sulfamate) (4), and 2-methoxyestradiol 17-O-sulfamate (5) are reported to 2.10, 1.85, and 1.64 A, respectively. Inhibitor 3 interacts with the active site Zn(II) ion through the 3-O-sulfamate, while inhibitors 4 and 5 bind through their 17-O-sulfamate. Comparison of the IC(50) values for CA II inhibition gave respective values of 56, 662, 2113, 169, 770, and 86 nM for estrone 3-O-sulfamate (1), 2-methoxyestradiol 3,17-O,O-bis(sulfamate) (2), 3, 4, 5, and 5'-((4H-1,2,4-triazol-4-yl)methyl)-3-chloro-2'-cyanobiphenyl-4-yl sulfamate (6), a nonsteroidal dual aromatase-sulfatase inhibitor. Inhibitors 2, 5, and 6 showed binding to a second adjacent site that is capable of binding both steroidal and nonsteroidal ligands. Examination of both IC(50) values and crystal structures suggests that 2-substituents on the steroid nucleus hinder binding via a 3-O-sulfamate, leading to coordination through a 17-O-sulfamate if present. These results underline the influence of small structural changes on affinity and mode of binding, the degree of flexibility in the design of sulfamate-based inhibitors, and suggest a strategy for inhibitors which interact with both the active site and the second adjacent binding site simultaneously that could be both potent and selective.


  • Organizational Affiliation

    Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath,Claverton Down, Bath BA2 7AY, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CARBONIC ANHYDRASE 2259Homo sapiensMutation(s): 0 
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
Binding Affinity Annotations 
IDSourceBinding Affinity
WZB Binding MOAD:  2X7T Ki: 232 (nM) from 1 assay(s)
BindingDB:  2X7T Ki: min: 232, max: 2420 (nM) from 2 assay(s)
IC50: 290 (nM) from 1 assay(s)
PDBBind:  2X7T Ki: 232 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.211 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.256α = 90
b = 40.832β = 104.49
c = 72.697γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-31
    Type: Initial release
  • Version 1.1: 2011-05-26
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-01-30
    Changes: Advisory, Data collection, Experimental preparation, Other
  • Version 1.4: 2019-02-06
    Changes: Data collection, Experimental preparation
  • Version 1.5: 2023-12-20
    Changes: Advisory, Data collection, Database references, Derived calculations, Other, Refinement description