4QJP

Crystal structure of human carbonic anhydrase isozyme XIII with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.172 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases

Dudutiene, V.Zubriene, A.Smirnov, A.Timm, D.D.Smirnoviene, J.Kazokaite, J.Michailoviene, V.Zaksauskas, A.Manakova, E.Grazulis, S.Matulis, D.

(2015) ChemMedChem 10: 662-687

  • DOI: https://doi.org/10.1002/cmdc.201402490
  • Primary Citation of Related Structures:  
    4QIY, 4QIZ, 4QJ0, 4QJM, 4QJO, 4QJP, 4QJW, 4QJX, 4QTL

  • PubMed Abstract: 

    Substituted tri- and tetrafluorobenzenesulfonamides were designed, synthesized, and evaluated as high-affinity and isoform-selective carbonic anhydrase (CA) inhibitors. Their binding affinities for recombinant human CA I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped-flow CO2 hydration assay. Variation of the substituents at the 2-, 3-, and 4-positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4-substituted-3,5,6-trifluorobenzenesulfonamides were effective CA XIII inhibitors with high selectivity over off-target CA I and CA II. 3,4-Disubstituted-2,5,6-trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4-disubstituted-3,5,6-trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA II, CA VII, tumor-associated CA IX and CA XII, and CA XIII. X-ray crystal structures of inhibitors bound in the active sites of several CA isoforms provide structure-activity relationship information for inhibitor binding affinities and selectivity.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius 02241 (Lithuania).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 13A [auth B],
B [auth A]
263Homo sapiensMutation(s): 0 
Gene Names: CA13
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q8N1Q1 (Homo sapiens)
Explore Q8N1Q1 
Go to UniProtKB:  Q8N1Q1
PHAROS:  Q8N1Q1
GTEx:  ENSG00000185015 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8N1Q1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V1F
Query on V1F

Download Ideal Coordinates CCD File 
E [auth B],
I [auth A]
3-(benzylamino)-2,5,6-trifluoro-4-[(2-phenylethyl)sulfonyl]benzenesulfonamide
C21 H19 F3 N2 O4 S2
IMGFYVAVEMQCNT-UHFFFAOYSA-N
CIT
Query on CIT

Download Ideal Coordinates CCD File 
H [auth A]CITRIC ACID
C6 H8 O7
KRKNYBCHXYNGOX-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
D [auth B]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
F [auth B],
J [auth A],
K [auth A],
L [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
V1F Binding MOAD:  4QJP Kd: 2.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.043α = 90
b = 57.544β = 90
c = 159.521γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction
HKL-2000data collection
XDSdata reduction
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-15
    Type: Initial release
  • Version 1.1: 2018-05-16
    Changes: Data collection, Refinement description
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description