4Q09

Crystal structure of chimeric carbonic anhydrase XII with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.143 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.

Dudutiene, V.Matuliene, J.Smirnov, A.Timm, D.D.Zubriene, A.Baranauskiene, L.Morkunaite, V.Smirnoviene, J.Michailoviene, V.Juozapaitiene, V.Mickeviciute, A.Kazokaite, J.Baksyte, S.Kasiliauskaite, A.Jachno, J.Revuckiene, J.Kisonaite, M.Pilipuityte, V.Ivanauskaite, E.Milinaviciute, G.Smirnovas, V.Petrikaite, V.Kairys, V.Petrauskas, V.Norvaisas, P.Linge, D.Gibieza, P.Capkauskaite, E.Zaksauskas, A.Kazlauskas, E.Manakova, E.Grazulis, S.Ladbury, J.E.Matulis, D.

(2014) J Med Chem 57: 9435-9446

  • DOI: https://doi.org/10.1021/jm501003k
  • Primary Citation of Related Structures:  
    4PYX, 4PYY, 4PZH, 4Q06, 4Q07, 4Q08, 4Q09, 4Q0L

  • PubMed Abstract: 

    Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, ‡Department of Bioinformatics, Institute of Biotechnology, §Department of Protein-DNA Interactions, Institute of Biotechnology, Vilnius University , V. A. Graičiu̅no 8, Vilnius LT-02241, Lithuania.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2260Homo sapiensMutation(s): 6 
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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V14
Query on V14

Download Ideal Coordinates CCD File 
C [auth A]3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide
C16 H23 F3 N2 O5 S2
HFJJAVOBUVMVFQ-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
D [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.143 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.835α = 90
b = 41.011β = 103.56
c = 71.006γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction
HKL-2000data collection
XDSdata reduction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-28
    Type: Initial release
  • Version 1.1: 2018-03-07
    Changes: Data collection
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description