4WR7

Crystal structure of human carbonic anhydrase isozyme I with 2,3,5,6-Tetrafluoro-4-(propylthio)benzenesulfonamide.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.199 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Intrinsic thermodynamics of 4-substituted-2,3,5,6-tetrafluorobenzenesulfonamide binding to carbonic anhydrases by isothermal titration calorimetry.

Zubriene, A.Smirnoviene, J.Smirnov, A.Morkunaite, V.Michailoviene, V.Jachno, J.Juozapaitiene, V.Norvaisas, P.Manakova, E.Grazulis, S.Matulis, D.

(2015) Biophys Chem 205: 51-65

  • DOI: https://doi.org/10.1016/j.bpc.2015.05.009
  • Primary Citation of Related Structures:  
    4WR7, 4WUP, 4WUQ, 4WW6, 4WW8

  • PubMed Abstract: 

    Para substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and entropy of binding to five CA isoforms were measured by ITC in two buffers of different protonation enthalpies. The pKa values of compound sulfonamide groups were measured potentiometrically and spectrophotometrically, and enthalpies of protonation were measured by ITC in order to evaluate the proton linkage contributions to the observed binding thermodynamics. Intrinsic means the affinity of a sulfonamide anion for the Zn bound water form of CAs. Fluorination of the benzene ring significantly enhanced the observed affinities as it increased the fraction of deprotonated ligand while having little impact on intrinsic affinities. Intrinsic enthalpy contributions to the binding affinity were dominant over entropy and were more exothermic for CA I than for other CA isoforms. Thermodynamic measurements together with the X-ray crystallographic structures of protein-ligand complexes enabled analysis of structure-activity relationships in this enzyme ligand system.


  • Organizational Affiliation

    Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius LT-02241, Lithuania. Electronic address: astzu@ibt.lt.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 1
A, B
260Homo sapiensMutation(s): 0 
Gene Names: CA1
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00915 (Homo sapiens)
Explore P00915 
Go to UniProtKB:  P00915
PHAROS:  P00915
GTEx:  ENSG00000133742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00915
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3TV
Query on 3TV

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
2,3,5,6-tetrafluoro-4-(propylsulfanyl)benzenesulfonamide
C9 H9 F4 N O2 S2
LKPIFWBRFVJTMY-UHFFFAOYSA-N
PEG
Query on PEG

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

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

Download Ideal Coordinates CCD File 
I [auth B],
K [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
ACT BindingDB:  4WR7 Ki: 1.08e+4 (nM) from 1 assay(s)
3TV BindingDB:  4WR7 Kd: 0.03 (nM) from 1 assay(s)
Binding MOAD:  4WR7 Kd: 2.00e-3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.199 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.353α = 90
b = 72.034β = 90
c = 121.11γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
AMoREphasing
SCALAdata scaling
REFMACrefinement

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: 2018-03-07
    Changes: Data collection
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description